ES2561659T3 - Aminopyrazole derivatives - Google Patents
Aminopyrazole derivatives Download PDFInfo
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- ES2561659T3 ES2561659T3 ES10806527.7T ES10806527T ES2561659T3 ES 2561659 T3 ES2561659 T3 ES 2561659T3 ES 10806527 T ES10806527 T ES 10806527T ES 2561659 T3 ES2561659 T3 ES 2561659T3
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- methanone
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- pyrazol
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A61K31/50—Pyridazines; Hydrogenated pyridazines
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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Abstract
Un compuesto representado por la siguiente fómula (I) general, o una sal farmacéuticamente aceptable del mismo:**Fórmula** en donde R1, R2, R3, y R4 cada uno representa independientemente el grupo enumerado a continuación: R1 representa hidrógeno, hidroxi, halógeno, ciano, nitro, haloalquilo C1-4, alquilo C1-6, alquenilo C2-6, alquinilo C2-6, cicloalquilo C3-7, arilo C6-10 alquilo C1-4, -OR5, -NR6R7, -(CR8R9)nZ1, -C(O)NR12R13, -SR14, -SOR15, -SO2R16, - NR17SO2R18, COOH, arilo C6-10 que es opcionalmente sustituido por uno o más grupos independientemente seleccionados del grupo P, heteroarilo de 5- a 10- miembros o heterociclilo de 3- a 10- miembros que es opcionalmente sustituido por uno o más grupos independientemente seleccionados del grupo Q, -COR19, -COOR20, - OC(O)R21, -NR22C(O)R23 -NR24C(S)R25, -C(S)NR26R27, -SO2NR28R29, -OSO2R30, -SO3R31, o -Si(R32)3; R2 representa hidrógeno, hidroxi, halógeno, ciano, nitro, haloalquilo C1-4, alquilo C1-6, alquenilo C2-6, alquinilo C2-6, cicloalquilo C3-7, arilo C6-10 alquilo C1-4, -OR5, -NR6R7, -(CR8R9)nZ1, -C(O)NR12R13, -SR14, -SOR15, -SO2R16, - NR17SO2R18, COOH, arilo C6-10 que es opcionalmente sustituido por uno o más grupos independientemente seleccionados del grupo P, heteroarilo de 5- a 10- miembros o heterociclilo de 3- a 10- miembros que es opcionalmente sustituido por uno o más grupos independientemente seleccionados del grupo Q, -COR19, -COOR20, - OC(O)R21, -NR22C(O)R23, -NR24C(S)R25, -C(S)NR26R27, -SO2NR28R29, -OSO2R30, -SO3R31, o -Si(R32)3; o R1 y R2, junto con un átomo unido al mismo, forman un heterociclilo de 3- a 10- miembros o heteroarilo de 5- a 10- miembros, en donde el heterociclilo o heteroarilo es opcionalmente sustituido por un halógeno; R3 representa hidrógeno, alquilo C1-5, arilo C6-10 alquilo C1-6, o haloalquilo C1-4; R4 representa hidrógeno, halógeno, alquilo C1-3, perfluoroalquilo C1-3, ciano, metanosulfonilo, hidroxilo, alcoxi, o amino; A representa indol o pirrol; R5 representa alquilo C1-5, cicloalquilo C3-7, cicloalquilo C3-7 alquilo C1-3, alquenilo C2-6, alquinilo C2-6, haloalquilo C1-4, alcoxi C1-3 alquilo C1-4, alcoxi C1-3 alcoxi C1-4 alquilo C1-4, aminoalquilo C1-4, alquilamino C1-4 alquilo C1-4, di(alquilo C1- 4)amino alquilo C1-4, arilo C6-10, arilo C6-10 alquilo C1-3, o heterociclilo de 3- a 10- miembros alquilo C1-3, heterociclilo de 3- a 10- miembros, heteroarilo de 5- a 10- miembros, heteroarilo de 5- a 10- miembros alquilo C1-3, monohidroxi alquilo C1-6, dihidroxialquilo C1-6, o trihidroxi alquilo C1-6 que es opcionalmente sustituido por uno o más grupos independientemente seleccionados del grupo Q; R6 y R7, que son iguales o diferentes, cada uno representa hidrógeno, alquilo C1-4, alquenilo C2-6, alquinilo C2-6, haloalquilo C1-4, alcoxi C1-3 alquilo C1-4, arilo C6-10 alquilo C1-3, heterociclilo de 3- a 10- miembros alquilo C1-3, heteroarilo de 5- a 10- miembros alquilo C1-3, monohidroxi alquilo C1-6, dihidroxi alquilo C1-6, trihidroxi alquilo C1-6, heterociclilo de 3- a 10- miembros, aminoalquilo C1-4, alquilamino C1-4 alquilo C1-4, di(alquilo C1-4)amino alquilo C1-4, o ciano(alquilo C1-3); o R6 y R7, junto con un átomo de nitrógeno unido al mismo, forman un heterociclilo de 3- a 10- miembros o heteroarilo de 5- a 10- miembros; n representa 1 a 3; R8 y R9, que son iguales o diferentes, cada uno representa hidrógeno, alquilo C1-4, o halógeno; o alternativamente, R8 y R9, junto con un átomo de carbono unido al mismo, forman un anillo cicloalifático; Z1 representa hidrógeno, NR10R11, -OH, o heterociclilo de 3- a 10- miembros o heteroarilo de 5- a 10- miembros que es opcionalmente sustituido por uno o más grupos independientemente seleccionados del grupo Q; R10 y R11, que son iguales o diferentes, cada uno representa alquilo C1-4, alquenilo C2-6, alquinilo C2-6, haloalquilo C1- 4, alcoxi C1-3 alquilo C1-4, ciano(alquilo C1-3), o alquilsulfonilo C1-3 alquilo C1-4; o alternativamente, R10 y R11, junto con un átomo de nitrógeno unido al mismo, forman un heterociclilo de 3- a 10- miembros o heteroarilo 5 de 5- a 10- miembros; R12 y R13, que son iguales o diferentes, cada uno representa hidrógeno, alquilo C1-4, alquenilo C2-6, alquinilo C2-6, haloalquilo C1-4, alcoxi C1-3 alquilo C1-4, arilo C6-10, heteroarilo de 5- a 10- miembros, heterociclilo de 3- a 10- miembros, arilo C6-10 alquilo C1-4, heterociclilo de 3- a 10- miembros alquilo C1-3, heteroarilo de 5- a 10- miembros alquilo C1-3, ciano(alquilo C1-3), alquilsulfonilo C1-3 alquilo C1-4, anillo cicloalifático de 3- a 10- miembros, heteroarilo de 5- a 10- miembros, o heterociclilo de 3- a 10- miembros; o alternativamente, R12 y R13, junto con un átomo de nitrógeno unido al mismo, forman un heterociclilo de 3- a 10- miembros o heteroarilo de 5- a 10- miembros que es opcionalmente sustituido por uno o más grupos independientemente seleccionados del grupo Q; R14 representa alquilo C1-4, alquenilo C2-6, alquinilo C2-6, haloalquilo C1-4, arilo C6-10 que es opcionalmente sustituido por uno o más grupos independientemente seleccionados del grupo P, o heteroarilo de 5- a 10- miembros o heterociclilo de 3- a 10- miembros que es opcionalmente sustituido por uno o más grupos independientemente seleccionados del grupo Q; R15 representa alquilo C1-4, alquenilo C2-6, alquinilo C2-6, haloalquilo C1-4, arilo C6-10 que es opcionalmente sustituido por uno o más grupos independientemente seleccionados del grupo P, o heteroarilo de 5- a 10- miembros o heterociclilo de 3- a 10- miembros que es opcionalmente sustituido por uno o más grupos independientemente seleccionados del grupo Q; R16 representa alquilo C1-4, alquenilo C2-6, alquinilo C2-6, haloalquilo C1-4, arilo C6-10 que es opcionalmente sustituido por uno o más grupos independientemente seleccionados del grupo P, o heteroarilo de 5- a 10- miembros o heterociclilo de 3- a 10- miembros que es opcionalmente sustituido por uno o más grupos independientemente seleccionados del grupo Q; R17 representa hidrógeno o alquilo C1-4; R18 representa alquilo C1-4, alquenilo C2-6, alquinilo C2-6, haloalquilo C1-4, arilo C6-10 que es opcionalmente sustituido por uno o más grupos independientemente seleccionados del grupo P, o heteroarilo de 5- a 10- miembros o heterociclilo de 3- a 10- miembros que es opcionalmente sustituido por uno o más grupos independientemente seleccionados del grupo Q; R19 representa hidrógeno, alquilo C1-4, cicloalquilo C3-7, haloalquilo C1-4, arilo C6-10, o heteroarilo de 5- a 10- miembros o heterociclilo de 3- a 10- miembros que es opcionalmente sustituido por uno o más grupos independientemente seleccionados del grupo Q; R20 representa alquilo C1-4, cicloalquilo C3-7, haloalquilo C1-4, arilo C6-10, heteroarilo de 5- a 10- miembros, o heterociclilo de 3- a 10- miembros; R21 representa alquilo C1-4, cicloalquilo C3-7, haloalquilo C1-4, arilo C6-10, heteroarilo de 5- a 10- miembros, o heterociclilo de 3- a 10- miembros; R22 representa hidrógeno, alquilo C1-4, o haloalquilo C1-4; R23 representa hidrógeno, alquilo C1-4, cicloalquilo C3-7, haloalquilo C1-4, arilo C6-10, heteroarilo de 5- a 10- miembros, o heterociclilo de 3- a 10- miembros; R24 representa hidrógeno, alquilo C1-4, o haloalquilo C1-4; R25 representa alquilo C1-4, cicloalquilo C3-7, haloalquilo C1-4, arilo C6-10, heteroarilo de 5- a 10- miembros, o heterociclilo de 3- a 10- miembros.A compound represented by the following general formula (I), or a pharmaceutically acceptable salt thereof: ** Formula ** wherein R1, R2, R3, and R4 each independently represents the group listed below: R1 represents hydrogen, hydroxy , halogen, cyano, nitro, C1-4 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-10 aryl C1-4 alkyl, -OR5, -NR6R7, - (CR8R9 ) nZ1, -C (O) NR12R13, -SR14, -SOR15, -SO2R16, - NR17SO2R18, COOH, C6-10 aryl which is optionally substituted by one or more groups independently selected from group P, heteroaryl from 5- to 10- 3- or 10-membered heterocyclyl or members which is optionally substituted by one or more groups independently selected from the group Q, -COR19, -COOR20, -OC (O) R21, -NR22C (O) R23 -NR24C (S) R25 , -C (S) NR26R27, -SO2NR28R29, -OSO2R30, -SO3R31, or -Si (R32) 3; R2 represents hydrogen, hydroxy, halogen, cyano, nitro, C1-4 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-10 aryl C1-4 alkyl, -OR5, - NR6R7, - (CR8R9) nZ1, -C (O) NR12R13, -SR14, -SOR15, -SO2R16, - NR17SO2R18, COOH, C6-10 aryl which is optionally substituted by one or more groups independently selected from the P group, heteroaryl of 5- to 10-members or 3- to 10-member heterocyclyl which is optionally substituted by one or more groups independently selected from the group Q, -COR19, -COOR20, - OC (O) R21, -NR22C (O) R23, -NR24C (S) R25, -C (S) NR26R27, -SO2NR28R29, -OSO2R30, -SO3R31, or -Si (R32) 3; or R1 and R2, together with an atom attached thereto, form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl, wherein the heterocyclyl or heteroaryl is optionally substituted by a halogen; R3 represents hydrogen, C1-5 alkyl, C6-10 aryl C1-6 alkyl, or C1-4 haloalkyl; R4 represents hydrogen, halogen, C1-3alkyl, C1-3 perfluoroalkyl, cyano, methanesulfonyl, hydroxyl, alkoxy, or amino; A represents indole or pyrrole; R5 represents C1-5 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1-3 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-3 alkoxy C1-4 alkyl, C1-3 alkoxy C1-4 C1-4 alkyl, C1-4 aminoalkyl, C1-4 alkylamino C1-4 alkyl, di (C1-4 alkyl) amino C1-4 alkyl, C6-10 aryl, C6-10 aryl C1-3 alkyl, or 3- to 10-membered heterocyclyl C1-3 alkyl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl C1-3 alkyl, monohydroxy C1-6 alkyl, dihydroxyalkyl C1-6, or trihydroxy C1-6 alkyl which is optionally substituted by one or more groups independently selected from the group Q; R6 and R7, which are the same or different, each represents hydrogen, C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-3 alkoxy C1-4 alkyl, C6-10 aryl C1 alkyl -3, 3- to 10-membered heterocyclyl C1-3 alkyl, 5- to 10-membered heteroaryl C1-3 alkyl, monohydroxy C1-6 alkyl, dihydroxy C1-6 alkyl, trihydroxy C1-6 alkyl, heterocyclyl 3 - 10-membered, C1-4 aminoalkyl, C1-4 alkylamino C1-4 alkyl, di (C1-4 alkyl) amino C1-4 alkyl, or cyano (C1-3 alkyl); or R6 and R7, together with a nitrogen atom attached thereto, form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl; n represents 1 to 3; R8 and R9, which are the same or different, each represents hydrogen, C1-4 alkyl, or halogen; or alternatively, R8 and R9, together with a carbon atom attached thereto, form a cycloaliphatic ring; Z1 represents hydrogen, NR10R11, -OH, or 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl which is optionally substituted by one or more groups independently selected from group Q; R10 and R11, which are the same or different, each represents C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-3 alkoxy C1-4 alkyl, cyano (C1-3 alkyl), or C1-3 alkylsulfonyl C1-4 alkyl; or alternatively, R10 and R11, together with a nitrogen atom attached thereto, form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl; R12 and R13, which are the same or different, each represents hydrogen, C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1-3 alkoxy C1-4 alkyl, C6-10 aryl, heteroaryl 5- to 10-membered, 3- to 10-membered heterocyclyl, C6-10 aryl C1-4 alkyl, 3- to 10-membered heterocyclyl C1-3 alkyl, 5- to 10-membered heteroaryl C1- alkyl 3, cyano (C1-3 alkyl), C1-3 alkyl sulfonyl C1-4 alkyl, 3- to 10-membered cycloaliphatic ring, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl; or alternatively, R12 and R13, together with a nitrogen atom attached thereto, form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl which is optionally substituted by one or more groups independently selected from group Q ; R14 represents C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C6-10 aryl which is optionally substituted by one or more groups independently selected from the P group, or 5- to 10-membered heteroaryl or 3- to 10-membered heterocyclyl which is optionally substituted by one or more groups independently selected from group Q; R15 represents C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C6-10 aryl which is optionally substituted by one or more groups independently selected from the P group, or 5- to 10-membered heteroaryl or 3- to 10-membered heterocyclyl which is optionally substituted by one or more groups independently selected from group Q; R16 represents C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C6-10 aryl which is optionally substituted by one or more groups independently selected from the P group, or 5- to 10-membered heteroaryl or 3- to 10-membered heterocyclyl which is optionally substituted by one or more groups independently selected from group Q; R17 represents hydrogen or C1-4 alkyl; R18 represents C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C6-10 aryl which is optionally substituted by one or more groups independently selected from the P group, or 5- to 10-membered heteroaryl or 3- to 10-membered heterocyclyl which is optionally substituted by one or more groups independently selected from group Q; R19 represents hydrogen, C1-4 alkyl, C3-7 cycloalkyl, C1-4 haloalkyl, C6-10 aryl, or 5- to 10-membered heteroaryl or 3- to 10-membered heterocyclyl which is optionally substituted by one or more groups independently selected from group Q; R20 represents C1-4 alkyl, C3-7 cycloalkyl, C1-4 haloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl; R21 represents C1-4 alkyl, C3-7 cycloalkyl, C1-4 haloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl; R22 represents hydrogen, C1-4 alkyl, or C1-4 haloalkyl; R23 represents hydrogen, C1-4 alkyl, C3-7 cycloalkyl, C1-4 haloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl; R24 represents hydrogen, C1-4 alkyl, or C1-4 haloalkyl; R25 represents C1-4 alkyl, C3-7 cycloalkyl, C1-4 haloalkyl, C6-10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl.
Description
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DESCRIPCIONDESCRIPTION
Derivados de aminopirazol Campo técnicoAminopyrazole derivatives Technical field
La presente invención se refiere a derivados de aminopirazol y usos de los mismos.The present invention relates to aminopyrazole derivatives and uses thereof.
Antecedentes de la técnicaPrior art
En la actualidad, la mayoría de los fármacos moleculares prometedores dirigidos contra el cáncer son los inhibidores del receptor de tirosina quinasa tales como erlotinib y lapatinib. Muchos de ellos son altamente eficaces contra los cánceres con mutación, amplificación, o sobreexpresión de los genes diana. Sin embargo, tales agentes moleculares dirigidos no pueden ejercer la eficacia contra los cánceres en los que se alteran los genes que no son sus objetivos. Por lo tanto, aún no existe un método terapéutico establecido que sea eficaz contra tales cánceres. Se espera que los inhibidores contra nuevos genes alterados en el cáncer hagan una gran contribución al tratamiento de pacientes con cáncer en quienes las drogas convencionales no tienen ningún efecto.At present, most promising molecular drugs directed against cancer are tyrosine kinase receptor inhibitors such as erlotinib and lapatinib. Many of them are highly effective against cancers with mutation, amplification, or overexpression of the target genes. However, such targeted molecular agents cannot exert efficacy against cancers in which genes that are not their targets are altered. Therefore, there is still no established therapeutic method that is effective against such cancers. Inhibitors against new genes altered in cancer are expected to make a great contribution to the treatment of cancer patients in whom conventional drugs have no effect.
Los receptores del factor de crecimiento de fibroblastos (FGFR) son quinasas pertenecientes a la familia del receptor tirosina quinasa. FGFR1, FGFR2, FGFR3, y FGFR4 constituyen la familia FGFR. El ligando es el factor de crecimiento de fibroblastos (FGF), y 22 tipos de proteínas estructuralmente similares forman una familia. Se sabe que cada FGFR se activa bajo la sobreexpresión, amplificación génica, mutación o translocación, y sirve como una causa de cáncer. La señal del FGFR sigue la vía MAPK o la vía PI3K/AKT. En el cáncer, se sabe que la señal está implicada en el crecimiento celular, angiogénesis, la migración celular, invasión, metástasis, y semejantes (Documento no patente 1).Fibroblast growth factor (FGFR) receptors are kinases belonging to the receptor tyrosine kinase family. FGFR1, FGFR2, FGFR3, and FGFR4 constitute the FGFR family. The ligand is the fibroblast growth factor (FGF), and 22 structurally similar types of proteins form a family. It is known that each FGFR is activated under overexpression, gene amplification, mutation or translocation, and serves as a cause of cancer. The FGFR signal follows the MAPK pathway or the PI3K / AKT pathway. In cancer, it is known that the signal is involved in cell growth, angiogenesis, cell migration, invasion, metastasis, and the like (Non-patent document 1).
Se sabe que el gen FGFR1 está amplificado en el cáncer de mama y el cáncer de pulmón de células no pequeñas (Documentos no-patente 2 y 3); mutado en el glioblastoma (Documento no-patente 4); translocado para generar una proteína de fusión en la leucemia mieloide aguda (Documento no-patente 5); y sobreexpresado en el cáncer de páncreas, cáncer de vejiga, cáncer de próstata, y cáncer de esófago. Adicionalmente, se sabe que FGFR1 se expresa en los neovasos y contribuyen en gran medida a la angiogénesis (Documento no-patente 6). Se sabe que el gen FGFR2 está amplificado en el cáncer de estómago y cáncer de mama (Documentos no-patente 7 y 8); mutado en el cáncer de endometrio (Documento no-patente 9); y sobreexpresado en cáncer de próstata, cáncer de esófago, cáncer de ovario, cáncer de páncreas, tumor cerebral, y cáncer de colon. Se sabe que el gen FGFR3 está translocado en el mleloma múltiple (Documento no-patente 10); mutado en el cáncer de vejiga (Documento no patente 11); y sobreexpresado en el cáncer de ovario, cáncer de pulmón de células no pequeñas, y carcinoma hepatocelular. Finalmente, se sabe que FGFR4 está mutado en el cáncer de pulmón, cáncer de ovario, cáncer de próstata, etc.; y sobreexpresado en cáncer de tiroides, cáncer de ovario, etc.It is known that the FGFR1 gene is amplified in breast cancer and non-small cell lung cancer (Non-patent documents 2 and 3); mutated in glioblastoma (Non-patent document 4); translocated to generate a fusion protein in acute myeloid leukemia (Non-patent document 5); and overexpressed in pancreatic cancer, bladder cancer, prostate cancer, and esophageal cancer. Additionally, it is known that FGFR1 is expressed in neo-vessels and contribute greatly to angiogenesis (Non-patent document 6). It is known that the FGFR2 gene is amplified in stomach cancer and breast cancer (Non-patent documents 7 and 8); mutated in endometrial cancer (Non-patent document 9); and overexpressed in prostate cancer, esophageal cancer, ovarian cancer, pancreas cancer, brain tumor, and colon cancer. It is known that the FGFR3 gene is translocated into the multiple myleoma (Non-patent document 10); mutated in bladder cancer (Non-patent document 11); and overexpressed in ovarian cancer, non-small cell lung cancer, and hepatocellular carcinoma. Finally, it is known that FGFR4 is mutated in lung cancer, ovarian cancer, prostate cancer, etc .; and overexpressed in thyroid cancer, ovarian cancer, etc.
Como se describió anteriormente, se ha sugerido fuertemente que todas las quinasas de la familia FGFR están Involucradas en el cáncer. Por lo tanto, la inhibición de quinasas de la familia del FGFR en tejidos de cáncer, puede ser un método terapéutico prometedor para el tratamiento de los tipos anteriores de cáncer.As described above, it has been strongly suggested that all FGFR family kinases are involved in cancer. Therefore, inhibition of FGFR family kinases in cancer tissues may be a promising therapeutic method for the treatment of previous types of cancer.
[Documentos de la técnica anterior][Documents of the prior art]
[Documento no-patente 1] Cytoklne & Growth Factor Revlews 16 (2005) 139-149 [Documento no-patente 2] Breast Cáncer Research 2007, 9:R23 [Documento no-patente 3] Cáncer Res 2005; 65(13): 5561-70 [Documento no-patente 4] PNAS (2005), 102(40), 14344-14349.[Non-patent document 1] Cytoklne & Growth Factor Revlews 16 (2005) 139-149 [Non-patent document 2] Breast Cancer Research 2007, 9: R23 [Non-patent document 3] Cancer Res 2005; 65 (13): 5561-70 [Non-patent document 4] PNAS (2005), 102 (40), 14344-14349.
[Documento no-patente 5] Acta Haematol 2002;107:101-107 [Documento no-patente 6] Nature Medicine 3, 887-89, 1997 [Documento no-patente 7] J Pathol. 2003 Nov;201(3):439-50 [Documento no-patente 8] Anal Cell Pathol. 2001;22(4):229-34 [Documento no-patente 9] Cáncer Res 2008;68(17):6902-7[Non-patent document 5] Acta Haematol 2002; 107: 101-107 [Non-patent document 6] Nature Medicine 3, 887-89, 1997 [Non-patent document 7] J Pathol. 2003 Nov; 201 (3): 439-50 [Non-patent document 8] Anal Cell Pathol. 2001; 22 (4): 229-34 [Non-patent document 9] Cancer Res 2008; 68 (17): 6902-7
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[Documento no-patente 10] Blood. 2003; 101: 4569-4575 [Documento no-patente 11] Nat Genet. 1999 Sep;23(1):18-20.[Non-patent document 10] Blood. 2003; 101: 4569-4575 [Non-patent document 11] Nat Genet. 1999 Sep; 23 (1): 18-20.
[Documento de la patente 1] FR 2831537 A1[Patent document 1] FR 2831537 A1
Esta solicitud de la patente se refiere a una composición que comprende derivados de bencimidazoles, composición que se considera útil para el tratamiento de enfermedades inflamatorias, cáncer, enfermedad pulmonar obstructiva crónica, asma, rinitis alérgica, o dermatitis atópica.This patent application refers to a composition comprising benzimidazole derivatives, a composition that is considered useful for the treatment of inflammatory diseases, cancer, chronic obstructive pulmonary disease, asthma, allergic rhinitis, or atopic dermatitis.
[Documento de la patente 2] WO 2010/010017 A1[Patent document 2] WO 2010/010017 A1
Esta solicitud de la patente describe compuestos antivirales heterocíclicos que tienen la siguiente fórmulaThis patent application describes heterocyclic antiviral compounds having the following formula
en donde R1, R2, R3, R4a, R4b, R4c, R5, R6, R9 y n son como se definen en este, los compuestos que se describen que son inhibidores de la polimerasa NS5b del virus de la Hepatitis C. También se describen las composiciones y métodos para el tratamiento de una infección por HCV y la inhibición de la replicación del HCVwherein R1, R2, R3, R4a, R4b, R4c, R5, R6, R9 and n are as defined herein, the compounds that are described as inhibitors of the NS5b polymerase of Hepatitis C virus. Compositions and methods for the treatment of an HCV infection and inhibition of HCV replication
[Documento de la patente 3] WO 2005/009973 A1[Patent document 3] WO 2005/009973 A1
Esta solicitud de la patente describe inhibidores de la quinasa p38 basados en heterociclo de 5 miembros, así como quinasa p38 basada en pirazol e imidazol, incluyendo p38alfa y p38beta quinasa, inhibidores, composiciones farmacéuticas que contienen los compuestos y métodos de uso de los compuestos y composiciones incluyendo métodos de tratamiento, prevención, o mejora de uno o más síntomas de enfermedades y trastornos mediados por p38 quinasa.This patent application describes p38 kinase inhibitors based on 5-membered heterocycle, as well as p38 kinase based on pyrazole and imidazole, including p38alpha and p38beta kinase, inhibitors, pharmaceutical compositions containing the compounds and methods of use of the compounds and Compositions including methods of treatment, prevention, or improvement of one or more symptoms of diseases and disorders mediated by p38 kinase.
Resumen de la invenciónSummary of the Invention
[Problemas que va a resolver la invención][Problems that the invention will solve]
Un objetivo de la presente invención es proveer compuestos de bajo peso molecular capaces de inhibir las quinasas de la familia del receptor del factor de crecimiento de fibroblastos (FGFR) en tejidos de cáncer.An objective of the present invention is to provide low molecular weight compounds capable of inhibiting kinases of the fibroblast growth factor receptor (FGFR) family in cancer tissues.
[Medios para resolver los problemas][Means to solve the problems]
Específicamente, la presente invención se refiere al contenido como se define en las reivindicaciones. Adicionalmente, la presente descripción o invención, respectivamente, incluye lo siguiente:Specifically, the present invention relates to the content as defined in the claims. Additionally, the present description or invention, respectively, includes the following:
[1] Un compuesto representado por la siguiente fórmula (I) general, o una sal farmacéuticamente aceptable del mismo:[1] A compound represented by the following general formula (I), or a pharmaceutically acceptable salt thereof:
<R*)<R *)
RR
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R2R2
NN
—R3—R3
( I )(I)
en donde R-i, R2, R3, y R4 cada uno representa independientemente el grupo enumerado a continuación:where R-i, R2, R3, and R4 each independently represent the group listed below:
R1 representa hidrógeno, hidroxi, halógeno, daño, nitro, haloalquilo C1-4, alquilo C1-6, alquenilo C2-6, alquinilo C2-6, cicloalquilo C3-7, arilo C6-10 alquilo C1-4, -OR5, -NR6R7, -(CRsRgjnZ-i, -C(0)NRi2Ri3, -SR14, -SOR15, -SO2R16, - NR17SO2R18, COOH, arilo C6-io que es opclonalmente sustituido por uno o más grupos independientemente seleccionados del grupo P, heteroarllo de 5- a 10- miembros o heterociclilo de 3- a 10- miembros que es opcionalmente sustituido por uno o más grupos Independientemente seleccionados del grupo Q, -COR19, -COOR20, - OC(0)R21, -NR22C(0)R23, -NR24C(S)R25, -C(S)NR26R27, -SO2NR28R29, -OSO2R30, -SO3R3I, O -SÍ(R32)3|R1 represents hydrogen, hydroxy, halogen, damage, nitro, C1-4 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-10 aryl C1-4 alkyl, -OR5, - NR6R7, - (CRsRgjnZ-i, -C (0) NRi2Ri3, -SR14, -SOR15, -SO2R16, - NR17SO2R18, COOH, aryl C6-io which is opclonally substituted by one or more groups independently selected from the P group, heteroaryl of 5- to 10-members or 3- to 10-member heterocyclyl which is optionally substituted by one or more groups Independently selected from the group Q, -COR19, -COOR20, -OC (0) R21, -NR22C (0) R23, -NR24C (S) R25, -C (S) NR26R27, -SO2NR28R29, -OSO2R30, -SO3R3I, OR -YES (R32) 3 |
R2 representa hidrógeno, hidroxi, halógeno, daño, nitro, haloalquilo Cm, alquilo C-m, alquenilo C2-6, alquinilo C2.6, cicloalquilo C3.7, arilo C6-io alquilo C1.4, -OR5, -NR6R7, -(CRsR^nZi, -C(0)NRi2Ri3, -SR14, -SOR15, -SO2R16, - NR17SO2R18, COOH, arilo Ce-10 que es opcionalmente sustituido por uno o más grupos independientemente seleccionados del grupo P, heteroarilo de 5- a 10- miembros o heterociclilo de 3- a 10- miembros que es opcionalmente sustituido por uno o más grupos independientemente seleccionados del grupo Q, -COR19, -COOR20, - OC(0)R21, -NR22C(0)R23, -NR24C(S)R25, -C(S)NR26R27, -SO2NR28R29, -OSO2R3O, -SO3R31, O -S¡(R32)3| OR2 represents hydrogen, hydroxy, halogen, damage, nitro, haloalkyl Cm, Cm alkyl, C2-6 alkenyl, C2.6 alkynyl, C3.7 cycloalkyl, C6-aryl-io C1.4 alkyl, -OR5, -NR6R7, - ( CRsR ^ nZi, -C (0) NRi2Ri3, -SR14, -SOR15, -SO2R16, - NR17SO2R18, COOH, aryl Ce-10 which is optionally substituted by one or more groups independently selected from group P, heteroaryl from 5-10 - 3- or 10-membered members or heterocyclyl which is optionally substituted by one or more groups independently selected from the group Q, -COR19, -COOR20, - OC (0) R21, -NR22C (0) R23, -NR24C (S ) R25, -C (S) NR26R27, -SO2NR28R29, -OSO2R3O, -SO3R31, O -S¡ (R32) 3 | O
R1 y R2, junto con un átomo unido al mismo, forman un heterociclilo de 3- a 10- miembros o heteroarilo de 5- a 10- miembros, en donde el heterociclilo o heteroarilo es opcionalmente sustituido por un halógeno;R1 and R2, together with an atom attached thereto, form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl, wherein the heterocyclyl or heteroaryl is optionally substituted by a halogen;
R3 representa hidrógeno, alquilo C1.5, arilo C6-io alquilo Ci.6l o haloalquilo C1.4;R3 represents hydrogen, C1.5 alkyl, C6-aryl-Ci.6l alkyl or C1.4 haloalkyl;
R4 representa hidrógeno, halógeno, alquilo C1-3, haloalquilo C1.4, hidroxi, ciano, nitro, alcoxi Cm, -(CH2)nZi, -NR6R7, - ORs, -C(0)NRi2Ri3, -SR14, -SOR15, -S02Ri6, NR17SO2R18, COOH, -COR19, -COOR20, -0C(0)R21, -NR22C(0)R23, - NR24C(S)R25, -C(S)NR26R27, -SO2NR28R29, -OSO2R30, -SO3R31, O-SÍ(R32)3|R4 represents hydrogen, halogen, C1-3 alkyl, C1.4 haloalkyl, hydroxy, cyano, nitro, alkoxy Cm, - (CH2) nZi, -NR6R7, - ORs, -C (0) NRi2Ri3, -SR14, -SOR15, -S02Ri6, NR17SO2R18, COOH, -COR19, -COOR20, -0C (0) R21, -NR22C (0) R23, - NR24C (S) R25, -C (S) NR26R27, -SO2NR28R29, -OSO2R30, -SO3R31, O-YES (R32) 3 |
A representa indol o pirrolA represents indole or pyrrole
R5 representa alquilo C1.5, cicloalquilo C3.7, cicloalquilo C3.7 alquilo C1.3, alquenilo C2.6, alquinilo C2.6, haloalquilo C1.4, alcoxi Ci_3 alquilo C1.4, alcoxi Ci_3 alcoxi Cm alquilo C1.4, aminoalqullo C1.4, alqullamlno C1.4 alquilo C1.4, di(alqullo C1-4)amlno alquilo C1.4, arilo C6-io, arilo C6-io alquilo C1.3, o heterociclilo de 3- a 10- miembros alquilo C1.3, heterociclilo de 3- a 10- miembros, heteroarilo de 5- a 10- miembros, heteroarilo de 5- a 10- miembros alquilo C1.3, monohldroxl alquilo Ci_6, dihidroxi alquilo Ci_6, o trihidroxi alquilo Ci.6 que es opcionalmente sustituido por uno o más grupos independientemente seleccionados del grupo Q;R5 represents C1.5 alkyl, C3.7 cycloalkyl, C3.7 cycloalkyl C1.3 alkyl, C2.6 alkenyl, C2.6 alkynyl, C1.4 haloalkyl, Ci_3 alkoxy C1.4 alkyl, Ci_3 alkoxy Cm C1 alkyl. 4, C1.4 aminoalkyl, C1.4 alkyl C1.4 alkyl, di (C1-4 alkyl) amyl C1.4 alkyl, C6-io aryl, C6-aryl C1.3 alkyl, or 3- to 10 heterocyclyl - C1.3 alkyl members, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl C1.3 alkyl, monohydroxy C1-6 alkyl, dihydroxy C1_6 alkyl, or trihydroxy C1 alkyl .6 which is optionally substituted by one or more groups independently selected from group Q;
R6 y R7, que son iguales o diferentes, cada uno representa hidrógeno, alquilo C1.4, alquenilo C2-6, alquinilo C2-6, haloalquilo C-m, alcoxi Ci_3 alquilo C1.4, arilo Ce-io alquilo Ci_3, heterociclilo de 3- a 10- miembros alquilo C1.3, heteroarilo de 5- a 10- miembros alquilo Ci_3, monohidroxi alquilo C-i-e, dihidroxi alquilo C-m, trihidroxi alquilo C1-6, heterociclilo de 3- a 10- miembros, aminoalquilo C1.4, alquilamino C-m alquilo C1.4, di(alquilo Ci_4)amino alquilo C1.4, o ciano(alquilo C1.3); o R@ y R7, junto con un átomo de nitrógeno unido al mismo, forman un heterociclilo de 3- a 10- mlembros o heteroarilo de 5- a 10- miembros;R6 and R7, which are the same or different, each represents hydrogen, C1.4 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cm haloalkyl, Ci_3 alkoxy C1.4 alkyl, aryl Ce-io Ci_3 alkyl, heterocyclyl of 3 - to 10- members C1.3 alkyl, 5- to 10-membered heteroaryl Ci_3 alkyl, monohydroxy Cie alkyl, dihydroxy Cm, trihydroxy C1-6 alkyl, 3- to 10-membered heterocyclyl, C1.4 aminoalkyl, alkylamino Cm C1.4 alkyl, di (Ci_4 alkyl) amino C1.4 alkyl, or cyano (C1.3 alkyl); or R @ and R7, together with a nitrogen atom attached thereto, form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl;
n representa 1 a 3;n represents 1 to 3;
Rs y Rg, que son iguales o diferentes, cada uno representa hidrógeno, alquilo C1.4, o halógeno; o alternativamente, Rs y Rg, junto con un átomo de carbono unido al mismo, forman un anillo cicloalifático; Z1 representa hidrógeno, NR10R11, -OH, o heterociclilo de 3- a 10- miembros o heteroarilo de 5- a 10- miembros que es opcionalmente sustituido por uno o más grupos Independientemente seleccionados del grupo Q;Rs and Rg, which are the same or different, each represents hydrogen, C1.4 alkyl, or halogen; or alternatively, Rs and Rg, together with a carbon atom attached thereto, form a cycloaliphatic ring; Z1 represents hydrogen, NR10R11, -OH, or 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl which is optionally substituted by one or more groups independently selected from group Q;
R10 y R11, que son iguales o diferentes, cada uno representa alquilo C-m, alquenilo C2-6, alquinilo C2-6, haloalquilo C1. 4, alcoxi C1.3 alquilo Cm, cianojalqullo Ci_3), o alquilsulfonilo C-i_3 alquilo C1.4; o alternativamente, R-|0y R11, junto conR10 and R11, which are the same or different, each represents C-m alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-haloalkyl. 4, C1.3 alkoxy C 1 alkyl, Ci_3 cyanojalqullo), or C 1-3 alkylsulfonyl C 1-4 alkyl; or alternatively, R- | 0 and R11, together with
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45Four. Five
un átomo de nitrógeno unido al mismo, forman un heterociclilo de 3- a 10- miembros o heteroarilo de 5- a 10- miembros;a nitrogen atom attached thereto, form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl;
R12 y Ri3, que son iguales o diferentes, cada uno representa hidrógeno, alquilo Ci_4, alquenilo C2-6, alquinilo C2-6, haloalquilo C-m, alcoxi C1.3 alquilo C1.4, arilo Ce-io, heteroarilo de 5- a 10- miembros, heterociclilo de 3- a 10- miembros, arilo Ce.10 alquilo C1.4, heterociclilo de 3- a 10- miembros alquilo C1.3, heteroarilo de 5- a 10- miembros alquilo C1-3, ciano(alquilo C1.3), alquilsulfonilo C1.3 alquilo C1-4, anillo cicloalifático de 3- a 10- miembros, heteroarilo de 5- a 10- miembros, o heterociclilo de 3- a 10- miembros; o alternativamente, R12 y R13, junto con un átomo de nitrógeno unido al mismo, forman un heterociclilo de 3- a 10- miembros o heteroarilo de 5- a 10- miembros que es opcionalmente sustituido por uno o más grupos independientemente seleccionados del grupo Q;R12 and Ri3, which are the same or different, each represents hydrogen, Ci_4 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cm haloalkyl, C1.3 alkoxy C1.4 alkyl, Ce-io aryl, 5- to heteroaryl 10-membered, 3- to 10-membered heterocyclyl, C 1-10 aryl, C1.4 alkyl, 3- to 10-membered heterocyclyl, C1.3 alkyl, 5- to 10-membered heteroaryl, C1-3 alkyl, cyano ( C1.3 alkyl), C1.3 alkyl sulfonyl C1-4 alkyl, 3- to 10-membered cycloaliphatic ring, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl; or alternatively, R12 and R13, together with a nitrogen atom attached thereto, form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl which is optionally substituted by one or more groups independently selected from group Q ;
R14 representa alquilo C1.4, alquenilo C2-6, alquinilo C2-6, haloalquilo C1.4, arilo C6-10 que es opcionalmente sustituido por uno o más grupos independientemente seleccionados del grupo P, o heteroarilo de 5- a 10- miembros o heterociclilo de 3- a 10- miembros que es opcionalmente sustituido por uno o más grupos independientemente seleccionados del grupo Q;R14 represents C1.4 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1.4 haloalkyl, C6-10 aryl which is optionally substituted by one or more groups independently selected from the P group, or 5- to 10-membered heteroaryl or 3- to 10-membered heterocyclyl which is optionally substituted by one or more groups independently selected from group Q;
R15 representa alquilo C1.4, alquenilo C2-6, alquinilo C2-6, haloalquilo C-m, arilo C6--io que es opcionalmente sustituido por uno o más grupos independientemente seleccionados del grupo P, o heteroarilo de 5- a 10- miembros o heterociclilo de 3- a 10- miembros que es opcionalmente sustituido por uno o más grupos independientemente seleccionados del grupo Q;R15 represents C1.4 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cm haloalkyl, C6-io aryl which is optionally substituted by one or more groups independently selected from the P group, or 5- to 10-membered heteroaryl or 3- to 10-membered heterocyclyl which is optionally substituted by one or more groups independently selected from group Q;
R16 representa alquilo C-m, alquenilo C2-6, alquinilo C2-6, haloalquilo Cm, arilo C6-10 que es opcionalmente sustituido por uno o más grupos independientemente seleccionados del grupo P, o heteroarilo de 5- a 10- miembros o heterociclilo de 3- a 10- miembros que es opcionalmente sustituido por uno o más grupos independientemente seleccionados del grupo Q;R16 represents C2-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 haloalkyl which is optionally substituted by one or more groups independently selected from the P group, or 5- to 10-membered heteroaryl or 3-heterocyclyl - 10-members which is optionally substituted by one or more groups independently selected from group Q;
R17 representa hidrógeno o alquilo C-m;R17 represents hydrogen or C-m alkyl;
Ría representa alquilo C-m, alquenilo C2-6, alquinilo C2-6, haloalquilo Cm, arilo C6-10 que es opcionalmente sustituido por uno o más grupos independientemente seleccionados del grupo P, o heteroarilo de 5- a 10- miembros o heterociclilo de 3- a 10- miembros que es opcionalmente sustituido por uno o más grupos independientemente seleccionados del grupo Q;Ria represents C2-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 haloalkyl which is optionally substituted by one or more groups independently selected from the P group, or 5- to 10-membered heteroaryl or 3-heterocyclyl - 10-members which is optionally substituted by one or more groups independently selected from group Q;
R19 representa hidrógeno, alquilo Cm, cicloalquilo C3.7, haloalquilo C-m, arilo C6--io, o heteroarilo de 5- a 10- miembros o heterociclilo de 3- a 10- miembros que es opcionalmente sustituido por uno o más grupos independientemente seleccionados del grupo Q;R19 represents hydrogen, Cm alkyl, C3.7 cycloalkyl, Cm haloalkyl, C6-io aryl, or 5- to 10-membered heteroaryl or 3- to 10-membered heterocyclyl which is optionally substituted by one or more independently selected groups from group Q;
R20 representa alquilo Cm, cicloalquilo C3-7, haloalquilo Cm, arilo C6-io, heteroarilo de 5- a 10- miembros, o heterociclilo de 3- a 10- miembros;R20 represents Cm alkyl, C3-7 cycloalkyl, Haloalkyl Cm, C6-io aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl;
R21 representa alquilo Cm, cicloalquilo C3.7, haloalquilo Cm, arilo C6--io, heteroarilo de 5- a 10- miembros, o heterociclilo de 3- a 10- miembros;R21 represents Cm alkyl, C3.7 cycloalkyl, Cm haloalkyl, C6-io aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl;
R22 representa hidrógeno, alquilo C-m, o haloalquilo Cm;R22 represents hydrogen, C-m alkyl, or haloalkyl Cm;
R23 representa hidrógeno, alquilo C-m, cicloalquilo C3.7, haloalquilo Cm, arilo C6-io, heteroarilo de 5- a 10- miembros, o heterociclilo de 3- a 10- miembros;R23 represents hydrogen, C-m alkyl, C3.7 cycloalkyl, Cm haloalkyl, C6-io aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl;
R24 representa hidrógeno, alquilo C-m, o haloalquilo C-m;R24 represents hydrogen, C-m alkyl, or C-m haloalkyl;
R25 representa alquilo Cm, cicloalquilo C3.7, haloalquilo Cm, arilo C6-io, heteroarilo de 5- a 10- miembros, o heterociclilo de 3- a 10- miembros;R25 represents Cm alkyl, C3.7 cycloalkyl, Cm haloalkyl, C6-io aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl;
R26 y R27, que son iguales o diferentes, cada uno representa hidrógeno, alquilo Cm, alquenilo C2-6, alquinilo C2-6, haloalquilo C-m, alcoxilo C1-3 alquilo C-m, arilo Ce.10, heteroarilo de 5- a 10- miembros, heterociclilo de 3- a 10- miembros, arilo Ce.10 alquilo C-m, heterociclilo de 3- a 10- miembros alquilo Cm, heteroarilo de 5- a 10- miembros alquilo C-m, ciano(alquilo Cm), alquilsulfonilo Cm alquilo Cm, o anillo cicloalifático de 3- a 10- miembros; o alternativamente, R26 y R27, junto con un átomo de nitrógeno unido al mismo, forman un heterociclilo de 3- a 10- miembros o heteroarilo de 5- a 10- miembros;R26 and R27, which are the same or different, each represents hydrogen, Cm alkyl, C2-6 alkenyl, C2-6 alkynyl, Haloalkyl Cm, C1-3 alkoxyl Cm, aryl Ce.10, heteroaryl 5- to 10- members, 3- to 10-membered heterocyclyl, Ce.10 -alkyl alkyl Cm, 3- to 10-membered alkyl heterocyclyl, 5- to 10-membered heteroaryl, Cm-alkyl, cyano (Cm-alkyl), alkylsulfonyl Cm-alkyl Cm , or 3- to 10-membered cycloaliphatic ring; or alternatively, R26 and R27, together with a nitrogen atom attached thereto, form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl;
R28 y R29, que son iguales o diferentes, cada uno representa hidrógeno, alquilo Cm, alquenilo C2-6, alquinilo C2-6, haloalquilo C-m, alcoxilo Cm alquilo C-m, arilo Ce.10, heteroarilo de 5- a 10- miembros, heterociclilo de 3- a 10- miembros, arilo Ce.10 alquilo C-m, heterociclilo de 3- a 10- miembros alquilo Cm, heteroarilo de 5- a 10- miembrosR28 and R29, which are the same or different, each represents hydrogen, Cm alkyl, C2-6 alkenyl, C2-6 alkynyl, Haloalkyl Cm, alkoxy Cm alkyl Cm, aryl Ce.10, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclyl, Ce. 10 alkyl, Cm alkyl, 3- to 10-membered heterocyclyl. Cm, 5- to 10-membered heteroaryl
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alquilo Ci-3, clano(alquilo C1-3), alquilsulfonilo C1.3 alquilo C1.4, o anillo cicloalifático de 3- a 10- miembros; o alternativamente, R28 y F?29, junto con un átomo de nitrógeno unido al mismo, forman un heterociclilo de 3- a 10- miembros o heteroarllo de 5- a 10- miembros;Ci-3 alkyl, clano (C1-3 alkyl), C1.3 alkylsulfonyl C1.4 alkyl, or 3- to 10-membered cycloaliphatic ring; or alternatively, R28 and F? 29, together with a nitrogen atom attached thereto, form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl;
R30 representa alquilo C1.4, cicloalquilo C3-7, haloalquilo C1.4, arilo C6-io, heteroarilo de 5- a 10- miembros, o heterociclilo de 3- a 10- miembros;R30 represents C1.4 alkyl, C3-7 cycloalkyl, C1.4 haloalkyl, C6-io aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl;
R31 representa alquilo C1.4, cicloalquilo C3-7, haloalquilo C1.4, arilo C6-io, heteroarilo de 5- a 10- miembros, o heterociclilo de 3- a 10- miembros;R31 represents C1.4 alkyl, C3-7 cycloalkyl, C1.4 haloalkyl, C6-io aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl;
R32 representa alquilo C-i_4 o arilo C6-10;R32 represents C-1-4 alkyl or C6-10 aryl;
<grupo P><group P>
halógeno, alquilo C1-4, haloalquilo C1-4, -OH, alcoxl C1-3, haloalcoxi C1-3, heterociclilamino de 3- a 10- miembros, - SO2R16, -CN, -NO2, y heterociclilo de 3- a 10- miembros;halogen, C1-4 alkyl, C1-4 haloalkyl, -OH, C1-3 alkoxy, C1-3 haloalkoxy, 3- to 10-membered heterocyclylamino, -SO2R16, -CN, -NO2, and 3- to 10 heterocyclyl - members;
<grupo Q><group Q>
halógeno, alquilo Ci_4, haloalquilo C1.4, -OH, alcoxi C1.3, monohidroxi alquilo Ci.6, dihidroxi alquilo Ci.6, trihidroxi alquilo C1-6, heterociclilo de 3- a 10- miembros amino, -SO2R16, -CN, -N02 cicloalquilo C3-7, -COR19, y heterociclilo de 3- a 10- miembros que es opcionalmente sustituido por un alquilo C1.4.halogen, Ci_4 alkyl, C1.4 haloalkyl, -OH, C1.3 alkoxy, monohydroxy Ci.6 alkyl, dihydroxy Ci.6 alkyl, trihydroxy C1-6 alkyl, 3- to 10-membered heterocyclyl amino, -SO2R16, - CN, -N02 C3-7 cycloalkyl, -COR19, and 3- to 10-membered heterocyclyl which is optionally substituted by a C1.4 alkyl.
De acuerdo con la invención, en el punto [1] descrito anteriormente,According to the invention, in the point [1] described above,
R4 representa hidrógeno, halógeno, alquilo C1.3, perfluoroalquilo Ci_3, ciano, metanosulfonilo, hidroxilo, alcoxi, o amino;R4 represents hydrogen, halogen, C1.3 alkyl, Ci_3 perfluoroalkyl, cyano, methanesulfonyl, hydroxyl, alkoxy, or amino;
A representa ¡ndol o pirrol;A represents ndol or pyrrole;
el citado compuesto representado por la fórmula (I) general no incluye la [5-amino-1-(2-metil-1H-bencimidazol-5-il)- 1H-pirazol-4-il]-[5-(4-tr¡fluorometil-fenil)-1H-indol-2-il]-metanona; ythe said compound represented by the general formula (I) does not include [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [5- (4- trfluoromethyl-phenyl) -1H-indol-2-yl] -methanone; Y
cicloalquilo se refiere a un grupo hidrocarburo alifático monovalente cíclico saturado o parcialmente saturado.Cycloalkyl refers to a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group.
[2] (no reivindicado) El compuesto de [1] o una sal farmacéuticamente aceptable del mismo, en donde A representa benceno, azaindol, benzofurano, benzotiofeno, benzotiazol, o quinolina.[2] (not claimed) The compound of [1] or a pharmaceutically acceptable salt thereof, wherein A represents benzene, azaindole, benzofuran, benzothiophene, benzothiazole, or quinoline.
[3] El compuesto de [1] o [2], o una sal farmacéuticamente aceptable del mismo, en donde R3 representa hidrógeno, alquilo C1-4, arilo C6-10 alquilo C1.4, o perfluoroalquilo C1.3.[3] The compound of [1] or [2], or a pharmaceutically acceptable salt thereof, wherein R3 represents hydrogen, C1-4 alkyl, C6-10 aryl C1.4 alkyl, or C1.3 perfluoroalkyl.
[4] El compuesto de uno cualquiera de [1] a [3], o una sal farmacéuticamente aceptable del mismo, en donde R4 representa hidrógeno, halógeno, alquilo C1.3, perfluoroalquilo C1.3, ciano, metanosulfonilo, hidroxilo, alcoxi, o amino.[4] The compound of any one of [1] to [3], or a pharmaceutically acceptable salt thereof, wherein R4 represents hydrogen, halogen, C1.3 alkyl, perfluoroalkyl C1.3, cyano, methanesulfonyl, hydroxyl, alkoxy , or amino.
[5] El compuesto de [1] o una sal farmacéuticamente aceptable del mismo, que se selecciona del grupo que consiste en:[5] The compound of [1] or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:
(1) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(1H-indol-2-il)-metanona;(1) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (1H-indole-2-yl) -methanone;
(2) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(6-pirrolidin-1-ilmetil-1H-ind ol-2-il)-metanona;(2) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (6-pyrrolidin-1-ylmethyl-1H-ind ol-2-yl ) -methanone;
(3) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(4-hidroxi-piperidin-1-ilmetil)-1H-indol-2-il]-metanona;(3) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [6- (4-hydroxy-piperidin-1-ylmethyl) -1H- indole-2-yl] -methanone;
(4) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(1H-pirrolo [3,2-c]piridin-2-il)-metanona;(4) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (1 H -pyrrolo [3,2-c] pyridin-2-yl) -metanone;
(5) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(6-piperazin-1-ilmetil-1H-ind ol-2-il)-metanona;(5) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (6-piperazin-1-ylmethyl-1H-ind ol-2-yl ) -methanone;
(6) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(2-morfolin-4-il-etoxi)-1 H-indol-2-il]-metanona;(6) [5-Amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6- (2-morpholin-4-yl-ethoxy) -1 H -indole-2-yl] -methanone;
(7) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(tetrahidro-piran-4-iloxi)-1 H-indol-2-il]-metanona;(7) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6- (tetrahydro-pyran-4-yloxy) -1 H-indole -2-yl] -methanone;
(8) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(4-cloro-1H-indol-2-il)-metanona;(8) [5-Amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (4-chloro-1 H -indole-2-yl) -methanone;
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(9) [5-am¡no-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-(5-bromo-1H-¡ndol-2-il)-metanona;(9) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1H-pyrazol-4-l] - (5-bromo-1H-dichol -2-yl) -methanone;
(10) [5-amino-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-(4-yodo-1H-¡ndol-2-il)-metanona;(10) [5-amino-1- (2-methyl-1H-benzimdazol-5-l) -1H-pyrazol-4-l] - (4-iodo-1H-¡ndol-2 -il) -methanone;
(11) 2-[5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-p¡razol-4-carbon¡l]-1H-¡ndol-5-carbonitrilo;(11) 2- [5-Amino-1- (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-carbon] -1 H -indole- 5-carbonitrile;
(12) [5-am¡no-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-(6-bromo-5-fluoro-1H-indol-2-il)-metanona;(12) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-l] - (6-bromo-5-fluoro- 1H-indole-2-yl) -methanone;
(13) [5-am¡no-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-(5-et¡n¡l-1H-¡ndol-2-il)-metanona;(13) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-l] - (5-et¡n¡l- 1H-¡-ol-2-yl) -methanone;
(14) [5-am¡no-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-[6-(2-fluoro-fenil)-1H-indol-2 -il]-metanona;(14) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-l] - [6- (2-fluoro-phenyl ) -1H-indole-2-yl] -methanone;
(15) [5-am¡no-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-[6-(3-fluoro-fenil)-1H-indol-2 -il]-metanona;(15) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-l] - [6- (3-fluoro-phenyl ) -1H-indole-2-yl] -methanone;
(16) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-[6-(4-fluoro-fenil)-1H-indol-2 -il]-metanona;(16) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-l] - [6- (4-fluoro -phenyl) -1H-indole-2-yl] -methanone;
(17) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-[6-(2-cloro-fenil)-1H-indol-2 -il]-metanona;(17) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-l] - [6- (2-chloro -phenyl) -1H-indole-2-yl] -methanone;
(18) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-[6-(3-cloro-fenil)-1H-indol-2 -il]-metanona;(18) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-l] - [6- (3-chloro -phenyl) -1H-indole-2-yl] -methanone;
(19) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-[6-(4-cloro-fenil)-1H-indol-2 -il]-metanona;(19) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-l] - [6- (4-chloro -phenyl) -1H-indole-2-yl] -methanone;
(20) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-[6-(2-tr¡fluorometil-fenil)-1H-indol-2-il]-metanona;(20) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1H-pyrazol-4-l] - [6- (2-tr Fluoromethyl-phenyl) -1H-indole-2-yl] -methanone;
(21) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-[6-(3-tr¡fluorometil-fenil)-1 H-indol-2-il]-metanona;(21) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H-p.razol-4-l] - [6- (3 -tr? fluoromethyl-phenyl) -1 H-indol-2-yl] -methanone;
(22) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-[6-(4-tr¡fluorometil-fenil)-1 H-indol-2-il]-metanona;(22) [5-am¡no-1- (2-met¡l-1H-benc¡m¡dazol-5-¡l) -1H-p¡razol-4-¡l] - [6- (4 -tr? fluoromethyl-phenyl) -1 H-indol-2-yl] -methanone;
(23) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(4-bromo-1H-¡ndol-2-il)-metanona;(23) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H-p.razol-4-l] - (4-bromo- 1H-¡-ol-2-yl) -methanone;
(24) [5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-il]-[6-(3-fluoro-pir¡d¡n-2-¡l)-1H-¡n dol-2-¡l]-metanona;(24) [5-amino-1- (2-methyl-1H-benzyldazol-5-l) -1H-pyrazol-4-yl] - [6- (3-fluoro-pyr d¡n-2-¡l) -1H-¡n dol-2-¡l] -methanone;
(25) [5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-il]-(6-metil-1H-indol-2-¡l)-metanona;(25) [5-amino-1- (2-methyl-1H-benzyldazol-5-l) -1H-pyrazol-4-yl] - (6-methyl-1H-indole-2 -L) -methanone;
(26) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-il]-[5-(4,4-difluoro-p¡per¡d¡na-1-carbon¡l)-1H-¡ndol-2-il]- metanona;(26) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-yl] - [5- (4,4- difluoro-p¡per¡d¡na-1-carbon¡l) -1H-¡ndol-2-il] - methanone;
(27) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-il]-[5-(3,3-d¡fluoro-p¡per¡d¡na-1-carbon¡l)-1H-¡ndol-2-il]- metanona;(27) [5-amine-1- (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-yl] - [5- (3,3-d Fluoro-p¡per¡d¡na-1-carbon¡l) -1H-¡ndol-2-il] - methanone;
(28) (2,2,2-trifluoro-etil)-amida del ácido 2-[5-am¡no-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-carbon¡l]-1H-¡ndol- 5-carboxílico;(28) 2- [5-Amine-1- (2-methyl-1H-benzyldazol-5-yl) -1H- (2,2,2-trifluoro-ethyl) -amide prazol-4-carbonl] -1 H -indole-5-carboxylic;
(29) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-p¡razol-4-¡l]-[6-(5-tr¡fluoromet¡l-p¡r¡d¡n-2-¡l)-1H-¡ndol-2-¡l]-metanona;(29) [5-am-1-1 (2-methyl-1H-benzyldazol-5-yl) -1 H-p.razole-4-l] - [6- (5- trfluoromet¡lp¡r¡d¡n-2-¡l) -1H-¡ndol-2-¡l] -methanone;
(30) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-il]-[6-(6-tr¡fluoromet¡l-p¡r¡d¡n-2-¡l)-1H-¡ndol-2-¡l]-metanona;(30) [5-am¡no-1- (2-met¡l-1H-benc¡m¡dazol-5-¡l) -1H-p¡razol-4-il] - [6- (6- trfluoromet¡lp¡r¡d¡n-2-¡l) -1H-¡ndol-2-¡l] -methanone;
(31) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-(5-cloro-piridin-2-il)-1 H-in dol-2-¡l]-metanona;(31) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6- (5-chloro-pyridin-2-yl) - 1 H-in dol-2-¡] -methanone;
(32) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-(4-metil-piridin-2-il)-1 H-¡ndol-2-il]-metanona;(32) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6- (4-methyl-pyridin-2-yl) - 1 H-¡-ol-2-yl] -methanone;
(33) [5-am¡no-1-(2-met¡l-1H-bencim¡dazol-5-¡l)-1H-p¡razol-4-¡l]-[6-(3-cloro-4-fluoro-fen¡l)-1 H-indol-2-il]-metanona;(33) [5-am-1-1 (2-methyl-1H-benzimdazol-5-l) -1H-p.razole-4-l] - [6- (3-chloro -4-fluoro-phenol) -1 H-indol-2-yl] -methanone;
(34) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-(3-trifluorometil-p¡ridin-2-il)-1 H-indol-2-il]-metanona;(34) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6- (3-trifluoromethyl-pridin-2-yl ) -1 H-indole-2-yl] -methanone;
(35) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-(4-trifluorometil-p¡ridin-2-il)-1 H-indol-2-il]-metanona;(35) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6- (4-trifluoromethyl-pridin-2-yl ) -1 H-indole-2-yl] -methanone;
(36) [5-amino-1-(6-fluoro-2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(1H-indol-2-il)-metanona;(36) [5-amino-1- (6-fluoro-2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (1H-indole-2-yl) -methanone;
(37) ácido 2-[5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-carbonil]-1H-indol-6-carboxílico;(37) 2- [5-Amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-carbonyl] -1 H -indole-6-carboxylic acid;
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(38) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(6-hidroximetil-1H-¡ndol-2-¡l)-metanona;(38) [5-amine-1- (2-methyl-1H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (6-hydroxymethyl-1 H -delol-2-¡ l) -methanone;
(39) [5-am¡no-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-{6-[2-(4-met¡l-p¡peraz¡n-1-¡l)-etox¡]-1H-¡ndol-2-¡l}- metanona;(39) [5-am¡no-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - {6- [2- (4-metll¡peraz¡ n-1-¡l) -etox¡] -1H-¡ndol-2-¡l} - methanone;
(40) [5-am¡no-1-(2-met¡l-1H-benc¡midazol-5-il)-1H-pirazol-4-il]-[6-(3-metil-oxetan-3-¡lmetox¡)-1H-¡ndol-2-¡l]-metanona;(40) [5-amine-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6- (3-methyl-oxetan-3 -¡Lmetox¡) -1H-¡ndol-2-¡l] -metanone;
(41) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-¡l]-[6-(3-fluoro-piperidin-1-¡lmet¡l)-1H-¡ndol-2-il]-metanona;(41) [5-am-1-1 (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-l] - [6- (3-fluoro- piperidin-1-¡lmet¡l) -1H-¡ndol-2-yl] -methanone;
(42) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-¡l]-(6-{[bis(2-metoxi-et¡l)am¡no ]-metil}-1 H-indol-2-il)- metanona;(42) [5-am-1-1 (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-l] - (6 - {[bis (2 -methoxy-etyl) amine] -methyl} -1 H-indol-2-yl) -methanone;
(43) [5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-¡l]-{6-[(metil-prop-2-¡n¡l-am¡no) metil]-1 H-indol-2-il}-(43) [5-amino-1- (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-l] - {6 - [(methyl-prop-2 -¡N¡l-am¡no) methyl] -1 H-indole-2-yl} -
metanona;methanone;
(44) [5-amino-1-(2-metil-1H-bendm¡dazol-5-¡l)-1H-p¡razol-4-¡l]-[6-(3,3-difluoro-pirrol¡d¡n-1-¡l metil)-1 H-indol-2-il]-(44) [5-amino-1- (2-methyl-1H-bendm¡dazol-5-¡l) -1H-p¡razol-4-¡l] - [6- (3,3-difluoro-pyrrole D¡n-1-ll methyl) -1 H-indole-2-yl] -
metanona;methanone;
(45) [5-amino-1-(2-metil-1H-bendm¡dazol-5-¡l)-1H-p¡razol-4-il]-[6-(2,5-dimetil-pirrolidin-1-il metil)-1 H-indol-2-il]-(45) [5-amino-1- (2-methyl-1H-bendm¡dazol-5-¡1) -1H-p¡razol-4-yl] - [6- (2,5-dimethyl-pyrrolidin- 1-yl methyl) -1 H-indole-2-yl] -
metanona;methanone;
(46) [5-am¡no-1-(2-metil-1H-bendm¡dazol-5-¡l)-1H-p¡razol-4-il]-[6-(3,3-difluoro-piperidin-1-ilmetil)-1H-indol-2-¡l]- metanona;(46) [5-am-1-1 (2-methyl-1H-bendmdadazol-5-1) -1 H-p.razole-4-yl] - [6- (3,3-difluoro- piperidin-1-ylmethyl) -1H-indole-2-l] - methanone;
(47) [5-am¡no-1-(2-metil-1H-bendmidazol-5-¡l)-1H-p¡razol-4-il]-[6-((S)-3-metil-morfolin-4-il metil)-1H-¡ndol-2-¡l]-(47) [5-am¡no-1- (2-methyl-1H-bendmidazol-5-l) -1H-p¡razol-4-yl] - [6 - ((S) -3-methyl- morpholin-4-yl methyl) -1H-¡ndol-2-¡l] -
metanona;methanone;
(48) [5-am¡no-1-(2-met¡l-1H-bendm¡dazol-5-¡l)-1H-pirazol-4-il]-(6-bromo-1H-indol-2-il)-metanona;(48) [5-am-1-1 (2-methyl-1H-blessmdazol-5-l) -1 H -pyrazol-4-yl] - (6-bromo-1H-indole-2 -il) -methanone;
(49) [5-amino-1-(2-metil-1H-bendm¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(5-yodo-1H-¡ndol-2-¡l)-metanona;(49) [5-amino-1- (2-methyl-1H-bendm¡dazol-5-¡l) -1H-p¡razol-4-¡l] - (5-iodo-1H-¡ndol-2 -L) -methanone;
(50) [5-amino-1-(2-metil-1H-bendm¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(1H-p¡rrolo[3,2-b]p¡r¡d¡n-2-¡l)-metanona;(50) [5-amino-1- (2-methyl-1H-bendm¡dazol-5-¡l) -1H-p¡razol-4-¡l] - (1H-prrolo [3,2- b] p¡r¡d¡n-2-¡l) -methanone;
(51) [5-am¡no-1-(2-met¡l-1H-bendm¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(5-bromo-6-tr¡fluoromet¡l-1H-indol-2-¡l)-metanona;(51) [5-am-1-1 (2-met-1-1-blessmdazol-5-1) -1 H-p.razol-4-1] - (5-bromine-6- trfluorometl-1H-indole-2-l) -methanone;
(52) [5-amino-1-(2-met¡l-1H-bendm¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(6-yodo-1H-¡ndol-2-N)-metanona;(52) [5-Amino-1- (2-Methyl-1H-Bendm¡dazol-5-L) -1H-p¡razol-4-L] - (6-iodo-1H-Dindole -2-N) -methanone;
(53) [5-am¡no-1-(2-met¡l-1H-bendm¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(4-met¡l-1H-indol-2-¡l)-metanona;(53) [5-am-1-1 (2-met-1-1-blessmdazol-5-1) -1 H-p.razole-4-1] - (4-meth) 1H-indole-2-l) -methanone;
(54) [5-amino-1-(2-met¡l-1H-bendm¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(4-¡soprop¡l-1H-¡ndol-2-¡l)-metanona;(54) [5-Amino-1- (2-Methyl-1H-Bendmdadazol-5-L) -1H-Pyrol-4-L] - (4-Sopropl-1H -¡Ndol-2-¡l) -methanone;
(55) [5-amino-1-(2-met¡l-1H-bendm¡dazol-5-¡l)-1H-p¡razol-4-¡l]-[5-(2-fluoro-fen¡l)-1H-indol-2 -il]-metanona;(55) [5-Amino-1- (2-Methyl-1H-Bendmdadazol-5-L) -1H-Pyrol-4-L] - [5- (2-Fluoro-fen L) -1H-indole-2-yl] -methanone;
(56) [5-am¡no-1-(2-met¡l-1H-benc¡midazol-5-¡l)-1H-p¡razol-4-¡l]-(5-benc¡l-1H-¡ndol-2-¡l)-metanona;(56) [5-am-1-1 (2-methyl-1 H -benzidamide-5-yl) -1 H-prazol-4-yl] - (5-benzyl) 1H-¡ndol-2-¡l) -methanone;
(57) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-il]-[5-(2-tr¡fluoromet¡l-fen¡l)-1H-¡ndol-2-¡l]-metanona;(57) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1H-prazol-4-yl] - [5- (2- trfluorometl-fen¡l) -1H-¡ndol-2-¡l] -methanone;
(58) [5-am¡no-1-(2-met¡l-1H-bendm¡dazol-5-¡l)-1H-p¡razol-4-¡l]-[5-(3-fluorofen¡l)-1H-indol-2-¡l]-metanona;(58) [5-am-1-1 (2-met-1-1-blessmdazol-5-1) -1 H-p.razole-4-1] - [5- (3-fluorophen) L) -1H-indole-2-l] -methanone;
(59) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[5-(3-trifluorometil-fenil)-1 H-indol-2-il]-metanona;(59) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [5- (3-trifluoromethyl-phenyl) -1 H-indole -2-yl] -methanone;
(60) [5-am¡no-1-(2-met¡l-1H-bendm¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(4-et¡n¡l-1H-indol-2-¡l)-metanona;(60) [5-am-1-1 (2-met-1-1-blessmdazol-5-1) -1 H-p.razol-4-1] - (4-et¡n) l-1H-indole-2-l) -methanone;
(61) [5-am¡no-1-(2-met¡l-1H-bendm¡dazol-5-¡l)-1H-pirazol-4-¡l]-(5H-[1,3]d¡oxolo[4,5-f]¡ndol-6-¡l)-metanona;(61) [5-am-1-1 (2-methyl-1H-blessmdazol-5-l) -1 H -pyrazol-4-l] - (5H- [1,3] d Oxolo [4,5-f] ¡ndol-6-¡l) -methanone;
(62) [5-am¡no-1-(7-fluoro-2-met¡l-1H-bendm¡dazol-5-il)-1H-p¡razol-4-¡l]-(1H-¡ndol-2-il)-metanona;(62) [5-am-no-1- (7-fluoro-2-methyl-1H-blessm¡dazol-5-yl) -1H-p¡razol-4-¡] - (1H-¡ ndol-2-yl) -methanone;
(63) [5-am¡no-1-(2-met¡l-1H-bendm¡dazol-5-¡l)-1H-p¡razol-4-¡l]-[5-(4-trifluoromet¡l-fen¡l)-1 H-¡ndol-2-¡l]-metanona;(63) [5-am-1-1 (2-met-1-1-blessmdazol-5-1) -1 H-p.razol-4-1] - [5- (4-trifluoromet L-fen¡l) -1 H-¡ndol-2-¡l-methanone;
(64) [5-am¡no-1-(2-metil-1H-bendm¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(5-butox¡-1H-indol-2-¡l)-metanona;(64) [5-am-no-1- (2-methyl-1H-bendm¡dazol-5-¡l) -1H-p¡razol-4-¡l] - (5-butox¡-1H-indole -2-¡) -methanone;
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(65) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[5-(1 -metil-piper¡din-4-M)-1 H -indol-2-¡l]-metanona;(65) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [5- (1-methyl-piperine-4-M ) -1 H -indole-2-1] -methanone;
(66) N-{2-[5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-carbon¡l]-1H-¡ndol-6-¡l}-metanosulfonam¡da;(66) N- {2- [5-amino-1- (2-methyl-1H-benzyldazol-5-α) -1H-prazol-4-carbonl] -1H -Ndol-6-¡l} -methanesulfonam¡da;
(67) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-(6-morfolin-4-M-p¡rid¡n-3-il)-1 H-indol-2-il]-metanona;(67) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6- (6-morpholin-4-Mp¡rid¡n -3-yl) -1 H-indol-2-yl] -methanone;
(68) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-(6-butil-1 H-indol-2-il)-metanona;(68) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (6-butyl-1 H-indole-2-yl) - methanone;
(69) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-(1 -metil-1 H-pirazol-4-il)-1 H-indol-2-il]-metanona;(69) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6- (1-methyl-1 H-pyrazole-4- il) -1 H-indol-2-yl] -methanone;
(70) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-(5-metoxi-p¡ridin-3-il)-1 H -indol-2-il]-metanona;(70) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6- (5-methoxy-pridin-3-yl ) -1 H -indole-2-yl] -methanone;
(71) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-(2-metoxi-p¡ridin-3-il)-1 H -indol-2-il]-metanona;(71) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6- (2-methoxy-pridin-3-yl ) -1 H -indole-2-yl] -methanone;
(72) [5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(6-c¡cloprop¡l-1H-¡ndol-2-¡l)-metanona;(72) [5-amino-1- (2-methyl-1H-benzyldazol-5-l) -1H-pyrolol-4-l] - (6-c¡cloprop¡ l-1H-¡ndol-2-¡l) -methanone;
(73) [5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-[6-(2-metox¡-fen¡l)-1H-¡ndo 1-2-¡l]-metanona;(73) [5-amino-1- (2-methyl-1H-benzyldazol-5-l) -1H-prazol-4-l] - [6- (2-methox ¡-Fen¡l) -1H-¡ndo 1-2-¡l] -methanone;
(74) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-M]-(6-fenil-1 H-indol-2-il)-metanona;(74) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-M] - (6-phenyl-1 H-indole-2-yl) - methanone;
(75) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-p¡ razol-4-M]-[6-(5-metanosulfon¡lo-piridin-3-il)-1 H-indol-2-M]- metanona;(75) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 Hp¡ razol-4-M] - [6- (5-methanesulfonlo-pyridin-3-yl ) -1 H-indole-2-M] - methanone;
(76) [5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-(6-¡soprop¡l-1H-¡ndol-2-¡l)-metanona;(76) [5-amino-1- (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-l] - (6-sopropl-1H -¡Ndol-2-¡l) -methanone;
(77) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-(6-p¡rid¡n-2-il-1 H-¡ndol-2-il)-metanona;(77) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - (6-p¡rid¡n-2-yl-1 H -¡Ndol-2-yl) -methanone;
(78) [5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-(5-c¡clopropil-1H-¡ndol-2-¡l)-metanona;(78) [5-amino-1- (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-l] - (5-c-cyclopropyl-1H- Ndol-2-¡l) -methanone;
(79) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-p¡razol-4-il]-(6-piridazin-3-il-1H-indol-2-il) -metanona;(79) [5-amine-1- (2-methyl-1H-benzyldazol-5-yl) -1H-pyrolol-4-yl] - (6-pyridazin-3- il-1H-indole-2-yl) -methanone;
(80) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5-isopropoxi-1H-indol-2-il)-metanona;(80) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (5-isopropoxy-1 H -indole-2-yl) -methanone;
(81) [5-am¡no-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[5-(2-metoxi-etoxi)-1H-indo 1-2-il]-metanona;(81) [5-amine-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [5- (2-methoxy-ethoxy) -1 H-indo 1 -2-yl] -methanone;
(82) [5-am¡no-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5-ciclopropilmetoxi-1H-indo 1-2-il)-metanona;(82) [5-amine-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (5-cyclopropylmethoxy-1H-indo 1-2-yl) - methanone;
(83) [5-am¡no-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(2,2-difluoro-5H-[1,3]dioxolo[4, 5-f]indol-6-il)-metanona;(83) [5-amine-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (2,2-difluoro-5 H- [1,3] dioxol [4,5-f] indole-6-yl) -methanone;
(84) [5-am¡no-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(3-cloro-piridin-2-il)-1H-in dol-2-il]-metanona;(84) [5-amine-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6- (3-chloro-pyridin-2-yl) - 1H-in dol-2-yl] -methanone;
(85) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(5-fluoro-piridin-2-il)-1H-in dol-2-il]-metanona;(85) [5-amine-1- (2-methyl-1H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6- (5-fluoro-pyridin-2-yl ) -1H-in dol-2-yl] -methanone;
(86) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(6-morfolin-4-il-piridazin-3-il)-1H-indol-2-¡l]- metanona;(86) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [6- (6-morpholin-4-yl-pyridazin-3-yl ) -1H-indole-2-¡] - methanone;
(87) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5-cloro-6-ciclopropilmetoxi-1H-indol-2-il)-metanona;(87) [5-amine-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (5-chloro-6-cyclopropylmethoxy-1H-indole- 2-yl) -methanone;
(88) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(2,4-difluoro-fenil)-1H-ind ol-2-il]-metanona;(88) [5-amine-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6- (2,4-difluoro-phenyl) - 1H-ind ol-2-yl] -methanone;
(89) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(6-p¡r¡dazin-4-il-1H-indol-2-il) -metanona;(89) [5-amine-1- (2-methyl-1H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (6-p¡r¡dazin-4-il- 1H-indole-2-yl) -methanone;
(90) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(3-fluoro-1H-indol-2-il)-metanona;(90) [5-amine-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (3-fluoro-1H-indole-2-yl) -metanone;
(91) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[5-(1-¡sopropil-piperidin-4-il)-6-trifluorometil-1H-indol-2- ¡l]-metanona;(91) [5-amine-1- (2-methyl-1H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [5- (1-sopropyl-piperidin-4- il) -6-trifluoromethyl-1H-indole-2-1] -methanone;
(92) 2-[5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-pirazol-4-carbon¡l]-1H-indol-6-carbonitrilo;(92) 2- [5-amine-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-carbonyl] -1H-indole-6-carbonitrile;
(93) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-¡l]-[5-(1,2,3,6-tetrahidro-piridin-4-il)-1H-indol-2-¡l]- metanona;(93) [5-Amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-α] - [5- (1,2,3,6-tetrahydro-pyridine- 4-yl) -1H-indole-2-l] - methanone;
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(94) [5-amino-1-(2-metil-1H-bencim¡dazol-5-¡l)-1H-p¡razol-4-il]-(5-piper¡d¡n-4-¡l-1H-¡ndol-2-¡l) -metanona;(94) [5-amino-1- (2-methyl-1H-benzimdazol-5-l) -1H-p¡razol-4-yl] - (5-piper¡d¡n-4-¡ l-1H-¡ndol-2-¡l) -methanone;
(95) [5-amino-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-il]-[5-((R)-3-fluoro-p¡rrol¡d¡n-1-¡l metil)-1 H-indol-2-M]-(95) [5-amino-1- (2-methyl-1H-benzamdazol-5-yl) -1 H -pyrazol-4-yl] - [5 - ((R) -3- fluoro-p¡rrol¡d¡n-1-l-methyl) -1 H-indole-2-M] -
metanona;methanone;
(96) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-(6-fluoro-5-piper¡din-4-M-1 H-in dol-2-il)-metanona;(96) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - (6-fluoro-5-piperine-4-M- 1 H-in dol-2-yl) -methanone;
(97) [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-fluoro-5-(1-metil-piperidin-4-il)-1 H-indol-2-il]- metanona;(97) [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6-fluoro-5- (1-methyl-piperidin-4 -il) -1 H-indol-2-yl] - methanone;
(98) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-¡l]-[5-(1-isopropil-piperidin-4-¡l)-1H-¡ndol-2-il]-metanona;(98) [5-am-1-1 (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-l] - [5- (1-isopropyl- piperidin-4-¡1) -1H-¡ndol-2-yl] -methanone;
(99) [5-amino-1-(2-metil-1H-bencim¡dazol-5-¡l)-1H-p¡razol-4-il]-[6-fluoro-5-(1-¡soprop¡l-p¡per¡d in-4-il)-1 H-indol-2-il]- metanona;(99) [5-amino-1- (2-methyl-1H-benzimdazol-5-l) -1H-p¡razol-4-yl] - [6-fluoro-5- (1-soprop ¡Lp¡per¡d in-4-il) -1 H-indol-2-il] - methanone;
(100) [5-amino-1-(2-metil-1H-bencimidazol-5-¡l)-1H-p¡razol-4-il]-(6-p¡r¡d¡n-3-¡l-1H-¡ndol-2-¡l)-metanona;(100) [5-amino-1- (2-methyl-1H-benzimidazol-5-1) -1H-p¡razol-4-yl] - (6-p¡r¡d¡n-3-¡ l-1H-¡ndol-2-¡l) -methanone;
(101) [5-amino-1-(2-metil-1H-bencimidazol-5-¡l)-1H-p¡razol-4-il]-[5-(6-morfolin-4-ilpiridin-3-il)-1H-¡ndol-2-il]-metanona;(101) [5-amino-1- (2-methyl-1H-benzimidazol-5-l) -1H-p¡razol-4-yl] - [5- (6-morpholin-4-ylpyridin-3- il) -1H-¡ndol-2-yl] -methanone;
(102) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-p¡razol-4-il]-(5-pirid¡n-3-il-1 H-indol-2-il)-metanona;(102) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 Hp¡razol-4-yl] - (5-pyridine-3-yl-1 H-indole -2-yl) -methanone;
(103) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[5-(6-piperazin-1 -il-piridin-3-il)-1 H-indol-2-M]- metanona;(103) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [5- (6-piperazin-1-yl-pyridin-3 -il) -1 H-indole-2-M] - methanone;
(104) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-p¡razol-4-il]-[5-(6-hidrox¡-p¡ridin-3-il)-1 H-indol-2-il]-metanona;(104) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 Hp¡razol-4-yl] - [5- (6-hydrox¡-p¡ridin-3- il) -1 H-indol-2-yl] -methanone;
(105) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-fluoro-5-(4-met¡l-p¡ perazin-1 -ilmetil)-1 H-indol-2-¡l]- metanona;(105) [5-Amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6-fluoro-5- (4-methyl perazin -1-methylmethyl) -1 H-indole-2-l] - methanone;
(106) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-¡l]-(6-fluoro-5-pirrolidin-1-ilmetil-1H-¡ndol-2-¡l)-metanona;(106) [5-amine-1- (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-l] - (6-fluoro-5-pyrrolidine -1-ilmethyl-1H-¡ndol-2-¡1) -methanone;
(107) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-¡l]-[6-(1-metil-piperidin-4-il)-1H -¡ndol-2-¡l]-metanona;(107) [5-am-1-1 (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-l] - [6- (1-methyl- piperidin-4-yl) -1H-¡ndol-2-¡l] -methanone;
(108) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-¡l]-[6-(4-morfolin-4-il-fenil)-1 H-¡ndol-2-¡l]-metanona;(108) [5-am-1-1 (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-l] - [6- (4-morpholin- 4-yl-phenyl) -1 H-¡ndol-2-¡1] -methanone;
(109) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-¡l]-[6-(3,4,5,6-tetrahidro-2H-[1,2’] bipirid¡n-5’-il)-1 H-indol- 2-¡l]-metanona;(109) [5-am-1-1 (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-l] - [6- (3,4, 5,6-tetrahydro-2H- [1,2 '] bipyridin-5'-yl) -1 H-indole-2-1] -methanone;
(110) [5-amino-1-(2-met¡l-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-(6-piperazin-1-il-pir¡din-3-¡l)-1 H-indol-2-il]- metanona;(110) [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6- (6-piperazin-1-yl-pir Din-3-¡l) -1 H-indol-2-yl] - methanone;
(111) [5-am¡no-1-(2-met¡l-1 H-benc¡m¡dazol-5-il)-1 H-pirazol-4-il]-[5-(6-metoxi-piridin-3-il)-1 H -¡ndol-2-¡l]-metanona;(111) [5-amine-1- (2-methyl-1 H-benzyldazol-5-yl) -1 H -pyrazol-4-yl] - [5- (6-methoxy -pyridin-3-yl) -1 H -indole-2-l] -methanone;
(112) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-¡l]-[5-((S)-3-metil-morfolin-4-¡l met¡l)-1 H-indol-2-il]-(112) [5-am-1-1 (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-l] - [5 - ((S) - 3-methyl-morpholin-4-ll) -1 H-indol-2-yl] -
metanona;methanone;
(113) [5-am¡no-1-(2-met¡l-1H-bendm¡dazol-5-il)-1H-pirazol-4-¡l]-[6-((R)-3-fluoro-pirrolid¡n-1-¡l metil)-1 H-indol-2-M]-(113) [5-am-1-1 (2-methyl-1H-blessmdazol-5-yl) -1 H -pyrazol-4-l] - [6 - ((R) -3- fluoro-pyrrolid¡n-1-methyl) -1 H-indole-2-M] -
metanona;methanone;
(114) [5-am¡no-1-(2-met¡l-1H-bendm¡dazol-5-il)-1H-pirazol-4-¡l]-[5-(2,5-dimetil-pirrolid¡n-1-¡l metil)-1 H-indol-2-il]-(114) [5-am-1-1 (2-methyl-1H-blessmdazol-5-yl) -1 H -pyrazol-4-l] - [5- (2,5-dimethyl- pyrrolid¡n-1-methyl) -1 H-indole-2-yl] -
metanona;methanone;
(115) [5-amino-1-(2-met¡l-1H-bendmidazol-5-il)-1H-p¡razol-4-¡l]-[5-(3-fluoro-piper¡d¡n-1-¡lmetil)-1H-indol-2-¡l]- metanona;(115) [5-amino-1- (2-meti-1H-bendmidazol-5-yl) -1H-p¡razol-4-¡] - [5- (3-fluoro-piper¡d¡ n-1-lmethyl) -1H-indole-2-l] - methanone;
(116) [5-amino-1-(2-met¡l-1H-bendmidazol-5-il)-1H-pirazol-4-¡l]-[5-(3,3-difluoro-piper¡d¡n-1-¡lmetil)-1H-indol-2-¡l]- metanona;(116) [5-amino-1- (2-meti-1H-bendmidazol-5-yl) -1H-pyrazol-4-l] - [5- (3,3-difluoro-piper¡d¡ n-1-lmethyl) -1H-indole-2-l] - methanone;
(117) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-il]-{6-[2-(4-metil-piperazin-1-¡l) p¡r¡d¡n-4-il]-1 H-indol-2-M}- metanona;(117) [5-am-no-1- (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-yl] - {6- [2- (4- methyl-piperazin-1-¡) p¡r¡d¡n-4-il] -1 H-indole-2-M} - methanone;
(118) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-il]-(6-p¡r¡d¡n-4-il-1H-indol-2-¡l)-metanona;(118) [5-am-1-1 (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-yl] - (6-p¡r¡d¡ n-4-yl-1H-indole-2-l) -methanone;
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(119) [5-amino-1-(2-metil-1H-bencimidazol-5-¡l)-1H-p¡razol-4-il]-[5-(4-fluoropiperidin-1-¡lmet¡l )-1H-indol-2-¡l]-(119) [5-amino-1- (2-methyl-1H-benzimidazol-5-1) -1H-p¡razol-4-yl] - [5- (4-fluoropiperidin-1-lmetl) ) -1H-indole-2-¡] -
metanona;methanone;
(120) [5-am¡no-1-(2-metil-1H-bencimidazol-5-¡l)-1H-p¡razol-4-il]-[5-(4,4-difluoro-piper¡d¡n-1-¡lmet¡l)-1H-indol-2-¡l]- metanona;(120) [5-am¡no-1- (2-methyl-1H-benzimidazol-5-¡1) -1H-p¡razol-4-yl] - [5- (4,4-difluoro-piper¡ d¡n-1-¡lmet¡l) -1H-indole-2-¡] - methanone;
(121) [5-am¡no-1-(2-difluorometil-1H-bencim¡dazol-5-¡l)-1H-p¡razol-4-il]-[5-(1-metil-piper¡d¡n-4 -il)-1 H-indol-2-il]- metanona;(121) [5-amine-1- (2-difluoromethyl-1H-benzimdadazol-5-¡l) -1H-p¡razol-4-yl] - [5- (1-methyl-piper¡ dn-4-yl) -1 H-indol-2-yl] -methanone;
(122) [5-am¡no-1-(2-difluorometil-1H-bencimidazol-5-¡l)-1H-p¡razol-4-il]-(1H-indol-2-il)-metanona;(122) [5-amine-1- (2-difluoromethyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (1 H -indol-2-yl) -methanone;
(123) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[5-(3,3-difluoro-pirrolidin-1 -¡I metil)-1 H-indol-2-M]-(123) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [5- (3,3-difluoro-pyrrolidin-1-¡ I methyl) -1 H-indole-2-M] -
metanona;methanone;
(124) [5-amino-1 -(2-metil-1 H-benci midazol-5-il)-1 H-pirazol-4-il]-[5-(1 -ciclopentil-piperid¡n-4-il )-1 H-indol-2-M]-(124) [5-amino-1 - (2-methyl-1 H-benci midazol-5-yl) -1 H-pyrazol-4-yl] - [5- (1-cyclopentyl-piperidine-4- il) -1 H-indole-2-M] -
metanona;methanone;
(125) [5-am¡no-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-p¡razol-4-il]-[5-(1 -ciclohexil-piperidin-4-il) -1H-¡ndol-2-il]-metanona;(125) [5-amine-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 Hp¡razol-4-yl] - [5- (1-cyclohexyl-piperidin-4-yl ) -1H-¡-ol-2-yl] -methanone;
(126) [5-am¡no-1-(2-met¡l-1H-bencim¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(4-bromo-1H-p¡rrol-2-¡l)-metanona;(126) [5-am-1-1 (2-methyl-1H-benzimdazol-5-l) -1H-p.razole-4-l] - (4-bromo-1H- prolrol-2-l) -methanone;
(127) [5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-( 1H-pirrol-2-il)-metanona;(127) [5-amino-1- (2-methyl-1H-benzyldazol-5-l) -1H-prazol-4-l] - (1H-pyrrole-2- il) -methanone;
(128) [5-am¡no-1-(2-met¡l-1H-benc¡midazol-5-¡l)-1H-p¡razol-4-¡l]-(4-fen¡l-1H-p¡rrol-2-¡l)-metanona;(128) [5-am-1-1 (2-methyl-1H-benzylmidazole-5-l) -1 H-p.razole-4-l] - (4-phenol) 1H-prolrol-2-l) -methanone;
(129) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-p¡razol-4-¡l]-[4-(3-cloro-fen¡l)-1H-p¡rrol-2-¡l]-metanona;(129) [5-am-1-1 (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-l] - [4- (3- chloro-phenol) -1H-pyrrol-2-l] -methanone;
(130) [5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-[4-(4-fluoro-fen¡l)-1H-p¡rrol-2-¡l]-metanona;(130) [5-amino-1- (2-methyl-1H-benzyldazol-5-l) -1H-prazol-4-l] - [4- (4-fluoro -fen¡l) -1H-prolrol-2-l] -methanone;
(131) [5-am¡no-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-[4-(3-fluoro-fen¡l)-1H-p¡rrol-2-il]-metanona;(131) [5-am¡no-1- (2-methyl-1H-benzmdadazol-5-l) -1H-p¡razol-4-¡] - [4- (3-fluoro -fen¡l) -1H-pyrrol-2-yl] -methanone;
(132) [5-am¡no-1-(2-met¡l-1H-bencim¡dazol-5-¡l)-1H-pirazol-4-¡l]-(6-morfolin-4-ilmet¡l-1H-¡n dol-2-il)-metanona;(132) [5-am-1-1 (2-methyl-1H-benzimdazol-5-l) -1 H -pyrazol-4-l] - (6-morpholin-4-ylmet) l-1H-¡n dol-2-yl) -methanone;
(133) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-pirazol-4-¡l]-[4-(2-morfolin-4-¡l-et¡lam¡no)-1H-indol-2-¡l]-metanona;(133) [5-am-1-1 (2-methyl-1H-benzimidazol-5-yl) -1 H -pyrazol-4-l] - [4- (2-morpholin-4-l] -et¡lam¡no) -1H-indole-2-¡] -methanone;
(134) [5-am¡no-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[5-(4-met¡l-p¡perazina-1-carbon¡l)-1H-¡ndol-2-¡l]- metanona;(134) [5-amine-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [5- (4-methyl perazine-1-carbon L) -1H-¡ndol-2-¡l] - methanone;
(135) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-il]-[6-(2-morfolin-4-¡l-et¡lam¡no)-1H-¡ndol-2-¡l]-metanona;(135) [5-amine-1- (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-yl] - [6- (2-morpholin-4 -¡L-et¡lam¡no) -1H-¡ndol-2-¡l] -methanone;
(136) [5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-il]-[5-(piperazina-1-carbon¡l)-1H-¡ndol-2-¡l]-metanona;(136) [5-amino-1- (2-methyl-1H-benzyldazol-5-yl) -1H-pyrazol-4-yl] - [5- (piperazine-1-carbonl) ) -1H-¡ndol-2-¡l] -methanone;
(137) [5-amino-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-il]-[4-(2-metoxi-etilam¡no)-1H-indol-2-¡l]-metanona;(137) [5-amino-1- (2-methyl-1H-benzamdazol-5-yl) -1 H -pyrazol-4-yl] - [4- (2-methoxy-ethylamine) -1H-indole-2-¡] -methanone;
(138) [5-amino-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-il]-[4-(2-hidroxi-1-h¡drox¡metil -et¡lam¡no)-1H-¡ndol-2-¡l]- metanona;(138) [5-amino-1- (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-yl] - [4- (2-hydroxy-1- h¡drox¡methyl -et¡lam¡no) -1H-¡ndol-2-¡l] - methanone;
(139) [5-amino-1-(2-metil-1H-bencim¡dazol-5-¡l)-1H-p¡razol-4-il]-[4-(2-piridin-4-il-et¡lam¡no)-1H-¡ndol-2-¡l]-metanona;(139) [5-amino-1- (2-methyl-1H-benzimdazol-5-yl) -1 H -pyrazol-4-yl] - [4- (2-pyridin-4-yl- et¡lam¡no) -1H-¡ndol-2-¡] -methanone;
(140) [5-amino-1-(2-metil-1H-bencimidazol-5-¡l)-1H-p¡razol-4-¡l]-[6-(2-metoxi-etilam¡no)-1H-¡ndol-2-¡l]-metanona;(140) [5-amino-1- (2-methyl-1H-benzimidazol-5-1) -1H-p¡razol-4-l] - [6- (2-methoxy-ethylamine) - 1H-¡-ol-2-¡] -methanone;
(141) [5-am¡no-1-(2-metil-1H-bencimidazol-5-¡l)-1H-p¡razol-4-¡l]-(6-morfolin-4-il-1H-¡ndol-2-il)-metanona;(141) [5-am¡no-1- (2-methyl-1H-benzimidazol-5-¡1) -1H-p¡razol-4-¡l] - (6-morpholin-4-yl-1H- Ndol-2-yl) -methanone;
(142) [5-am¡no-1-(2-metil-1H-benc¡midazol-5-il)-1H-p¡razol-4-¡l]-(4-morfol¡n-4-¡l-1H-¡ndol-2-¡l)-metanona;(142) [5-am-1-1 (2-methyl-1 H -benzimidazol-5-yl) -1 H-prazol-4-l] - (4-morphol-4-¡ l-1H-¡ndol-2-¡l) -methanone;
(143) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(4-morfol¡n-4-ilmet¡l-1H-¡ndol-2-¡l)-metanona;(143) [5-am¡no-1- (2-met¡l-1H-benc¡m¡dazol-5-¡l) -1H-p¡razol-4-¡l] - (4-morfol¡ n-4-ilmet¡l-1H-¡ndol-2-¡l) -methanone;
(144) [5-am¡no-1-(2-met¡l-1H-benc¡midazol-5-¡l)-1H-pirazol-4-¡l]-(5-morfol¡n-4-¡lmet¡l-1H-¡ndol-2-¡l)-metanona;(144) [5-am-1-1 (2-methyl-1 H -benzimidazol-5-l) -1 H -pyrazol-4-l] - (5-morphol-4 Lmet¡l-1H-¡ndol-2-¡l) -methanone;
(145) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-¡l]-[5-(morfol¡na-4-carbon¡l)-1H-¡ndol-2-¡l]-metanona;(145) [5-am-1-1 (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-l] - [5- (morphol- 4-carbon¡l) -1H-¡ndol-2-¡] -methanone;
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(146) [5-am¡no-1-(2-¡soprop¡l-1H-benc¡m¡dazol-5-il)-1H-p¡razol-4-¡l]-(1H-¡ndol-2-¡l)-metanona;(146) [5-am-n-1- (2-soprop¡l-1H-benz¡m¡dazol-5-yl) -1H-p¡razol-4-¡l] - (1H-¡ndol -2-¡) -methanone;
(147) [5-am¡no-1-(2-prop¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-(1H-¡ndol-2-¡l)-metanona;(147) [5-am-1-1 (2-propyl-1H-benzyldazol-5-l) -1H-pyrazol-4-l] - (1H-linole-2 -L) -methanone;
(148) [5-am¡no-1-(1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-il]-(1H-¡ndol-2-¡l)-metanona;(148) [5-am¡no-1- (1H-benc¡m¡dazol-5-¡l) -1H-p¡razol-4-il] - (1H-¡ndol-2-¡l) - methanone;
(149) [5-am¡no-1 -(2-trifluorometil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-(1 H-indol-2-il)-metanona;(149) [5-amine-1 - (2-trifluoromethyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (1 H-indole-2-yl) -methanone;
(150) [5-am¡no-1 -(2-etil-1 H-bencim¡dazol-5-il)-1 H-pirazol-4-il]-( 1 H-indol-2-il)-metanona;(150) [5-amine-1 - (2-ethyl-1 H-benzimdazol-5-yl) -1 H -pyrazol-4-yl] - (1 H-indole-2-yl) - methanone;
(151) [5-am¡no-1-(2-benc¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-(1H-¡ndol-2-¡l)-metanona;(151) [5-am-1-1 (2-benzyl-1H-benzyldazol-5-l) -1H-pyrazol-4-l] - (1H-linole-2 -L) -methanone;
(152) 1 -(4-{2-[5-amino-1 -(2-met¡l-1 H-bencimidazol-5-il)-1 H-pirazol-4-carbonil]-1 H-indol-5-ilmet¡l}-p¡ perazin-1 -il)- etanona;(152) 1 - (4- {2- [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-carbonyl] -1 H-indole- 5-ylmethyl} -pi perazin-1-yl) -ethanone;
(153) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-[5-(4-metanosulfon¡lo-p¡peraz¡n -1 -ilmetil)-1 H-indol-2- il]-metanona;(153) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-l] - [5- (4-methanesulfon Lo-p¡peraz¡n -1 -ylmethyl) -1 H-indole-2- yl] -methanone;
(154) [5-am¡no-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-p¡razol-4-il]-(5-piperazin-1 -ilmetil-1 H-ind ol-2-¡l)-metanona;(154) [5-amine-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 Hp¡razol-4-yl] - (5-piperazin-1-ylmethyl-1 H-ind ol-2-¡l) -methanone;
(155) 1 -(4-{2-[5-amino-1 -(2-met¡l-1 H-bencimidazol-5-il)-1 H-pirazol-4-carbonil]-1 H-indol-6-ilmet¡l}-p¡ perazin-1 -il)- etanona;(155) 1 - (4- {2- [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-carbonyl] -1 H-indole- 6-ylmethyl} -pi perazin-1-yl) -ethanone;
(156) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-(4-metil-piperazin-1 -ilmetil)-1 H-indol-2-il]- metanona;(156) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6- (4-methyl-piperazin-1-methylmethyl) - 1 H-indole-2-yl] -methanone;
(157) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-M]-[5-(4-metil-piperazin-1 -Mmetil)-1 H-indol-2-M]- metanona;(157) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-M] - [5- (4-methyl-piperazin-1-methyl) - 1 H-indole-2-M] - methanone;
(158) [5-am¡no-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-(5-pirrolidin-1 -ilmetil-1 H-ind ol-2-il)-metanona;(158) [5-amine-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (5-pyrrolidin-1-ylmethyl-1 H-ind ol-2-yl) -methanone;
(159) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-p¡razol-4-¡l]-(4-fluoro-1H-¡ndol-2-il)-metanona;(159) [5-am-1-1 (2-methyl-1H-benzyldazol-5-yl) -1H-p.razole-4-l] - (4-fluoro-1H -¡Ndol-2-yl) -methanone;
(160) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-p¡razol-4-il]-(5-fluoro-1H-¡ndol-2-il)-metanona;(160) [5-amine-1- (2-methyl-1H-benzyldazol-5-yl) -1H-prazol-4-yl] - (5-fluoro-1H- Ndol-2-yl) -methanone;
(161) [5-am¡no-1-(2-met¡l-1H-bencim¡dazol-5-¡l)-1H-p¡razol-4-il]-(6-fluoro-1H-¡ndol-2-il)-metanona;(161) [5-am-1-1 (2-methyl-1H-benzimdazol-5-yl) -1 H -pyrazol-4-yl] - (6-fluoro-1H-¡ ndol-2-yl) -methanone;
(162) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-il]-(1H-pirrolo[2,3-b]p¡ridin-2-il)-metanona;(162) [5-am-1-1 (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-yl] - (1 H -pyrrolo [2 , 3-b] pridin-2-yl) -methanone;
(163) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(5-fluoro-6-morfol¡n-4-ilmetil-1H-indol-2-il)-metanona;(163) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H-p.razol-4-l] - (5-fluoro- 6-morphol-4-ylmethyl-1H-indol-2-yl) -methanone;
(164) ácido 2-[5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-carbonil]-1H-indol-5-carboxílico;(164) 2- [5-Amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-carbonyl] -1 H -indole-5-carboxylic acid;
(165) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5-metoxi-1H-indol-2-il)-metanona;(165) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (5-methoxy-1H-indole-2-yl) -methanone;
(166) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(4,6-dimetoxi-1H-indol-2-il)-metanona;(166) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (4,6-dimethoxy-1H-indole-2-yl) -methanone ;
(167) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-p¡razol-4-il]-(4-metoxi-1H-indol-2-il)-metanona;(167) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-p¡razol-4-yl] - (4-methoxy-1H-indole-2-yl) -methanone ;
(168) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(6-metoxi-1H-indol-2-il)-metanona;(168) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (6-methoxy-1H-indole-2-yl) -methanone;
(169) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(4,6-dimetil-1H-indol-2-il)-metanona;(169) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (4,6-dimethyl-1H-indole-2-yl) -methanone ;
(170) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5-íert-butil-1H-indol-2-il)-metanona;(170) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (5-íert-butyl-1H-indole-2-yl) -methanone ;
(171) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5-isopropil-1H-indol-2-il)-metanona;(171) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (5-isopropyl-1H-indole-2-yl) -methanone;
(172) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5-benciloxi-1H-indol-2-il)-metanona;(172) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (5-benzyloxy-1 H -indole-2-yl) -methanone;
(173) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(4-benciloxi-1H-indol-2-il)-metanona;(173) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (4-benzyloxy-1 H -indole-2-yl) -methanone;
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(174) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-il]-(5,6-dimetoxi-1H-indol-2-¡l)-metanona;(174) [5-amine-1- (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-yl] - (5,6-dimethoxy-1H- indole-2-l) -methanone;
(175) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-il]-(6-ferf-butil-1H-indol-2-il)-metanona;(175) [5-amine-1- (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-yl] - (6-ferf-butyl-1H- indole-2-yl) -methanone;
(176) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-il]-(5-fluoro-4-trifluorometil-1H-¡ndol-2-¡l)-metanona;(176) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H-p.razol-4-yl] - (5-fluoro-4 -trifluoromethyl-1H-¡ndol-2-¡1) -methanone;
(177) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-il]-(5-fenox¡-1H-¡ndol-2-¡l)-metanona;(177) [5-am-1-1 (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-yl] - (5-phenoxy) 1H-¡ndol-2-¡l) -methanone;
(178) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(6-metilsulfan¡l-1H-¡ndol-2-¡l)-metanona;(178) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H-p.razol-4-l] - (6-methyl sulfan) l-1H-¡ndol-2-¡l) -methanone;
(179) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(4-ferf-but¡l-1H-indol-2-¡l)-metanona;(179) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1H-p.razole-4-l] - (4-ferf- but¡l-1H-indole-2-l) -methanone;
(180) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(5-metil-1H-¡ndol-2-¡l)-metanona;(180) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H-p.razol-4-l] - (5-methyl- 1H-¡ndol-2-¡l) -methanone;
(181) [5-amino-1 -(2-met¡l-1 H-benc¡m¡dazol-5-¡l)-1 H-p¡razol-4-il]-(5-etil-1 H-indol-2-il)-metanona;(181) [5-Amino-1 - (2-methyl-1 H-benzyldazol-5-l) -1 Hp.razol-4-yl] - (5-ethyl-1 H- indole-2-yl) -methanone;
(182) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(5-fluoro-6-trifluoromet¡l-1H-¡ndol-2-¡l)-metanona;(182) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H-p.razol-4-l] - (5-fluoro- 6-trifluorometl-1H-¡ndol-2-¡l) -methanone;
(183) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-il]-(6-fluoro-5-metox¡-1H-¡ndol-2 -il)-metanona;(183) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-yl] - (6-fluoro-5 -methox¡-1H-¡ndol-2-yl) -methanone;
(184) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(6-cloro-5-metoxi-1H-¡ndol-2-¡l)-metanona;(184) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1H-prazol-4-l] - (6-chloro- 5-methoxy-1H-landol-2-l) -methanone;
(185) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(5-cloro-6-metoxi-1H-¡ndol-2-¡l)-metanona;(185) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H-p.razol-4-l] - (5-chloro- 6-methoxy-1H-landol-2-l) -methanone;
(186) [5-am¡no-1-(2-met¡l-1H-benc¡midazol-5-¡l)-1H-p¡razol-4-¡l]-(6-¡sopropox¡-1H-¡ndol-2-¡l)-metanona;(186) [5-am-1-1 (2-methyl-1H-benzylmidazol-5-l) -1H-p.razol-4-l] - (6-sopropox) 1H-¡ndol-2-¡l) -methanone;
(187) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(6-bencilox¡-1H-¡ndol-2-¡l)-metanona;(187) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1H-pyrolol-4-l] - (6-benzyloxy) -1H-¡ndol-2-¡l) -methanone;
(188) [5-am¡no-1-(2-met¡l-1H-bencim¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(4-¡sopropox¡-1H-indol-2-¡l)-metanona;(188) [5-am-1-1 (2-methyl-1H-benzimdadazol-5-l) -1 H-p.razol-4-l] - (4-sopropox) 1H-indole-2-l) -methanone;
(189) [5-am¡no-1-(2-metil-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-il]-(2,3-d¡h¡dro-6H-[1,4]dioxino[2, 3-f]indol-7-il)- metanona;(189) [5-amine-1- (2-methyl-1H-benzimdazol-5-yl) -1H-pyrazol-4-yl] - (2,3-d¡h¡dro- 6H- [1,4] dioxino [2,3-f] indole-7-yl) -methanone;
(190) [5-amino-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-il]-(4,6-di-fe/f-but¡l-1H-indol-2-il) -metanona;(190) [5-amino-1- (2-methyl-1H-benzimdazol-5-yl) -1 H -pyrazol-4-yl] - (4,6-di-fe / f-but L-1H-indole-2-yl) -methanone;
(191) 2-[5-amino-1-(2-metil-1 H-benc¡m¡dazol-5-¡l)-1 H-pirazol-4-carbonil]-1 H-indol-4-carbonitrilo;(191) 2- [5-Amino-1- (2-methyl-1 H-benzyldazol-5-l) -1 H -pyrazol-4-carbonyl] -1 H-indole-4-carbonitrile ;
(192) [5-amino-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-il]-(5-imidazol-1-¡l-1H-indol-2-il) -metanona;(192) [5-Amino-1- (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-yl] - (5-imidazol-1-l-1) 1H-indole-2-yl) -methanone;
(193) [5-amino-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-il]-(5-trifluoromet¡lsulfanil-1H-indol-2-il)-metanona;(193) [5-amino-1- (2-methyl-1H-benzyldazol-5-yl) -1H-p¡razol-4-yl] - (5-trifluorometlsulfanyl-1H-indole -2-yl) -methanone;
(194) [5-amino-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-il]-(5-metilsulfan¡l-1H-indol-2-il )-metanona;(194) [5-Amino-1- (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-yl] - (5-methylsulfan-l-1H-indole -2-yl) -methanone;
(195) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(5-metanosulfon¡lo-1H-indol-2-¡l)-metanona;(195) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H-p.razol-4-l] - (5-methanesulfon) lo-1H-indole-2-l) -methanone;
(196) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pi razol-4-il]-[6-(4,4-difluoro-piperidin-1 -ilmetil)-1 H-indol-2-M]- metanona;(196) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pi razol-4-yl] - [6- (4,4-difluoro-piperidin-1 - ilmethyl) -1 H-indole-2-M] - methanone;
(197) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-(4-fluoro-pi peridin-1 -ilmetil)-1 H-indol-2-M]- metanona;(197) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6- (4-fluoro-pi peridin-1-methylmethyl) -1 H-indole-2-M] - methanone;
(198) [5-amino-1-(2-metil-1H-bencimidazol-5-¡l)-1H-p¡razol-4-il]-[6-(oxetan-3-iloxi)-1H-indol-2-¡l]-metanona;(198) [5-amino-1- (2-methyl-1H-benzimidazol-5-l) -1H-p¡razol-4-yl] - [6- (oxetan-3-yloxy) -1H-indole -2-¡] -methanone;
(199) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-¡l)-1H-p¡razol-4-il]-(6-hidrox¡-1H-indol-2-il)-metanona;(199) [5-amine-1- (2-methyl-1H-benzimidazol-5-l) -1H-p¡razol-4-yl] - (6-hydroxy-1H-indole- 2-yl) -methanone;
(200) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-p¡razol-4-¡l]-(6-metanosulfonilo-1H-indol-2-¡l)-metanona;(200) [5-amine-1- (2-methyl-1H-benzimidazol-5-yl) -1 H -pyrazol-4-l] - (6-methanesulfonyl-1H-indole-2 -L) -methanone;
(201) [5-am¡no-1-(2-metil-1H-bencimidazol-5-¡l)-1H-p¡razol-4-¡l]-(4,5-dibromo-1H-pirrol-2-¡l)-metanona;(201) [5-am¡no-1- (2-methyl-1H-benzimidazol-5-¡1) -1H-p¡razol-4-¡l] - (4,5-dibromo-1H-pyrrole- 2-¡) -methanone;
(202) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-p¡razol-4-il]-(4,5-difen¡l-1 H-pirrol-2-il)-metanona;(202) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 Hp¡razol-4-yl] - (4,5-diphenyl-1 H-pyrrole-2 -il) -methanone;
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(203) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(4,5-dipiridin-3-il-1H-pirrol-2-il)-metanona;(203) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (4,5-dipyridin-3-yl-1H-pyrrole-2- il) -methanone;
(204) [5-amino-1-(2-metil-3H-bencimidazol-5-il)-1H-pirazol-4-il]-(6-cloro-1H-indol-2-il)-metanona;(204) [5-amino-1- (2-methyl-3H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (6-chloro-1H-indole-2-yl) -methanone;
(205) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5-cloro-1H-indol-2-il)-metanona;(205) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (5-chloro-1H-indole-2-yl) -methanone;
(206) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(1H-indol-3-il)-metanona;(206) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (1H-indole-3-yl) -methanone;
(207) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(1H-indol-6-il)-metanona;(207) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (1H-indole-6-yl) -methanone;
(208) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5-bromo-6-fluoro-1H-indol-2-il)-metanona;(208) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (5-bromo-6-fluoro-1H-indole-2-yl) -metanone;
(209) [5-amino-1-(2-etil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5-bromo-6-fluoro-1H-indol-2-il) -metanona;(209) [5-amino-1- (2-ethyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (5-bromo-6-fluoro-1 H -indole-2-yl) -metanone;
(210) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5-trifluorometil-1H-indol-2-il)-metanona;(210) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (5-trifluoromethyl-1 H -indole-2-yl) -methanone;
(211) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5-trifluorometoxi-1H-indol-2-il)-metanona;(211) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (5-trifluoromethoxy-1 H-indol-2-yl) -methanone;
(212) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(4,6-dicloro-1H-indol-2-il)-metanona;(212) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (4,6-dichloro-1H-indole-2-yl) -methanone ;
(213) 5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(6-bromo-4-fluoro-1H-indol-2-il)-metanona;(213) 5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (6-bromo-4-fluoro-1H-indole-2-yl) - methanone;
(214) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(6-trifluorometoxi-1H-indol-2-il)-metanona;(214) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (6-trifluoromethoxy-1 H -indole-2-yl) -methanone;
(215) [5-amino-1-(2-etil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5-trifluorometoxi-1H-indol-2-il)-metanona;(215) [5-amino-1- (2-ethyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (5-trifluoromethoxy-1 H -indole-2-yl) -methanone;
(216) [5-amino-1-(2-etil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5-trifluorometil-1H-indol-2-il)-metanona;(216) [5-amino-1- (2-ethyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (5-trifluoromethyl-1 H -indole-2-yl) -methanone;
(217) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5,6-dicloro-1H-indol-2-il)-metanona;(217) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (5,6-dichloro-1H-indole-2-yl) -methanone ;
(218) [5-amino-1-(2-etil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(6-bromo-5-fluoro-1H-indol-2-il) -metanona;(218) [5-amino-1- (2-ethyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (6-bromo-5-fluoro-1H-indole-2-yl) -metanone;
(219) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(4,5-dicloro-1H-indol-2-il)-metanona;(219) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (4,5-dichloro-1H-indole-2-yl) -methanone ;
(220) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(4,6-difluoro-1H-indol-2-il)-metanona;(220) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (4,6-difluoro-1H-indole-2-yl) -methanone ;
(221) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(3-cloro-piridin-4-il)-1H-in dol-2-il]-metanona;(221) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6- (3-chloro-pyridin-4-yl) -1 H- in dol-2-il] -methanone;
(222) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(6-metil-piridina-3-il)-1H-indol-2-il]-metanona;(222) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6- (6-methyl-pyridine-3-yl) -1 H- indole-2-yl] -methanone;
(223) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-(5-fluoro-piridin-3-il)-1 H-in dol-2-il]-metanona;(223) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6- (5-fluoro-pyridin-3-yl) - 1 H-in dol-2-yl] -methanone;
(224) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(2-trifluorometil-piridin-3-il)-1H-indol-2-il]-metanona;(224) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6- (2-trifluoromethyl-pyridin-3-yl) -1 H- indole-2-yl] -methanone;
(225) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(5-cloro-2-metoxi-piridin-3-il)-1H-indol-2-il]- metanona;(225) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [6- (5-chloro-2-methoxy-pyridin-3-yl ) -1H-indole-2-yl] - methanone;
(226) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(5-cloro-piridin-3-il)-1H-in dol-2-il]-metanona;(226) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6- (5-chloro-pyridin-3-yl) -1 H- in dol-2-il] -methanone;
(227) [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-(6-tiofen-3-il-1 H-indol-2-il) -metanona;(227) [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - (6-thiophen-3-yl-1 H-indole-2 -il) -methanone;
(228) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(4-cloropiridin-3-il)-1H-in dol-2-il]-metanona;(228) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [6- (4-chloropyridin-3-yl) -1H-in dol -2-yl] -methanone;
(229) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-(6-tiofen-2-il-1 H-indol-2-il) -metanona;(229) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (6-thiophen-2-yl-1 H-indole-2 -il) -methanone;
(230) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-(3-fluoro-piridin-4-il)-1 H-in dol-2-il]-metanona;(230) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6- (3-fluoro-pyridin-4-yl) - 1 H-in dol-2-yl] -methanone;
(231) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(2-trifluorometil-piridin-4-il)-1H-indol-2-il]-metanona;(231) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [6- (2-trifluoromethyl-pyridin-4-yl) -1H- indole-2-yl] -methanone;
(232) [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[5-(3,3-difluoro-pirrolidi na-1-carbonil)-1 H-indol-2-il]- metanona;(232) [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [5- (3,3-difluoro-pyrrolidi na-1- carbonyl) -1 H-indol-2-yl] -methanone;
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(233) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-il]-[5-(2,6-d¡met¡l-morfol¡na-4-carbon¡l)-1H-indol-2-il]- metanona;(233) [5-amine-1- (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-yl] - [5- (2,6-d Metyl-morpholna-4-carbonl) -1H-indol-2-yl] -methanone;
(234) [5-am¡no-1-(2-met¡l-1 H-benc¡m¡dazol-5-il)-1 H-pirazol-4-il]-[5-([1,4’] b¡p¡per¡d¡n¡l-1 ’-carbon¡l)-1 H-indol-2-il]- metanona;(234) [5-amine-1- (2-methyl-1 H-benzyldazol-5-yl) -1 H -pyrazol-4-yl] - [5 - ([1, 4 '] b¡p¡per¡d¡n¡l-1' -carbon¡l) -1 H-indol-2-yl] - methanone;
(235) [5-am¡no-1-(2-met¡l-1H-bendm¡dazol-5-il)-1H-pirazol-4-il]-{5-[4-(2,2,2-tr¡fluoro-et¡l)-p¡perazina-1-carbonil]-1H- ¡ndol-2-¡l}-metanona;(235) [5-am-1-1 (2-methyl-1H-blessmdazol-5-yl) -1 H -pyrazol-4-yl] - {5- [4- (2,2, 2-trfluoro-etl) -p¡perazine-1-carbonyl] -1H- ndol-2-ll-methanone;
(236) [5-am¡no-1-(2-met¡l-1H-bendm¡dazol-5-il)-1H-pirazol-4-il]-{5-[4-(2-h¡drox¡-et¡l)-p¡peraz¡na-1-carbon¡l]-1H-indol-2- ¡l}-metanona;(236) [5-am-1-1 (2-methyl-1H-blessmdazol-5-yl) -1 H -pyrazol-4-yl] - {5- [4- (2-h) drox¡-et¡l) -p¡peraz¡na-1-carbon¡l] -1H-indole-2- l} -methanone;
(237) [5-am¡no-1-(2-met¡l-1H-bendm¡dazol-5-il)-1H-p¡razol-4-il]-[5-(3,3,4,4-tetrafluoro-p¡rrol¡d¡na-1-carbon¡l)-1H-¡ndol- 2-¡l]-metanona;(237) [5-am-1-1 (2-methyl-1H-blessmdazol-5-yl) -1 H-p.razole-4-yl] - [5- (3,3,4 , 4-tetrafluoro-prolrol-dna-1-carbonl) -1H-landol-2-ll-methanone;
(238) [5-am¡no-1-(2-met¡l-1H-bendm¡dazol-5-il)-1H-p¡razol-4-il]-[5-((R)-3-fluoro-p¡rrol¡d¡na-1-carbonil)-1H-¡ndol-2-¡l]- metanona;(238) [5-am-1-1 (2-methyl-1H-blessmdazol-5-yl) -1 H-p.razole-4-yl] - [5 - ((R) -3 -fluoro-p¡rrol¡d¡na-1-carbonyl) -1H-¡ndol-2-¡] - methanone;
(239) [5-am¡no-1-(2-met¡l-1H-bendm¡dazol-5-il)-1H-p¡razol-4-il]-[5-((S)-3-fluroro-p¡rrol¡d¡na-1-carbonil)-1H-¡ndol-2-¡l]- metanona;(239) [5-am-1-1 (2-met-1-1-blessmdazol-5-yl) -1 H-p.razole-4-yl] - [5 - ((S) -3 -fluroro-p¡rrol¡d¡na-1-carbonyl) -1H-¡ndol-2-¡] - methanone;
(240) [5-am¡no-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-il]-[4-(4-metox¡-fen¡l)-1H-p¡rrol-2-¡l]-metanona;(240) [5-am¡no-1- (2-methyl-1H-benzmdadazol-5-l) -1H-p¡razol-4-yl] - [4- (4-methox¡ -fen¡l) -1H-prolrol-2-l] -methanone;
(241) [5-am¡no-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-il]-[4-(3-metox¡-fen¡l)-1H-p¡rrol-2-¡l]-metanona;(241) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1H-p.razole-4-yl] - [4- (3-methox) -fen¡l) -1H-prolrol-2-l] -methanone;
(242) [5-am¡no-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-il]-[4,5-bis-(3-fluoro-fen¡l)-1H-p¡rrol-2-¡l]-metanona;(242) [5-am-1-1- (2-methyl-1H-benzyldazol-5-l) -1H-p.razole-4-yl] - [4,5-bis- ( 3-fluoro-phenol) -1H-pyrrol-2-l] -methanone;
(243) [5-am¡no-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-il]-[4,5-bis-(4-metoxi-fenil)-1H -p¡rrol-2-¡l]-metanona;(243) [5-am-1-1- (2-methyl-1H-benzyldazol-5-l) -1H-p.razole-4-yl] - [4,5-bis- ( 4-methoxy-phenyl) -1 H -pyrrol-2-l] -methanone;
(244) [5-am¡no-1-(2-met¡l-1H-bendm¡dazol-5-¡l)-1H-p¡razol-4-¡l]-[4-(2,4-d¡fluoro-fen¡l)-1H-p¡rrol-2-¡l]-metanona;(244) [5-am-1-1 (2-met-1-1-blessmdazol-5-1) -1 H-p.razol-4-1] - [4- (2,4 -d¡fluoro-fen¡l) -1H-pyrrol-2-¡l-methanone;
(245) [5-am¡no-1-(2-met¡l-1H-bendm¡dazol-5-il)-1H-p¡razol-4-¡l]-[4-(4-tr¡fluorometox¡-fen¡l)-1H-pirrol-2-il]-metanona;(245) [5-am-1-1 (2-met-1-1-blessmdazol-5-yl) -1 H-p.razole-4-l] - [4- (4-tr. fluoromethoxy-phenyl) -1H-pyrrol-2-yl] -methanone;
(246) [5-amino-1-(2-met¡l-1H-bendmidazol-5-¡l)-1H-p¡razol-4-¡l]-[4,5-b¡s-(3-metox¡-fen¡l)-1H -pirrol-2-il]-metanona;(246) [5-amino-1- (2-meti-1H-bendmidazol-5-l) -1H-p¡razol-4-l] - [4,5-b¡s- (3 -methox¡-fen¡l) -1 H -pyrrol-2-yl] -methanone;
(247) [5-amino-1-(2-met¡l-1H-bendmidazol-5-¡l)-1H-p¡razol-4-¡l]-benzofurano-2-¡l-metanona;(247) [5-amino-1- (2-methyl-1H-bendmidazol-5-α) -1 H -pyrazol-4-α] -benzofuran-2-α-methanone;
(248) [5-amino-1-(2-met¡l-1H-bendmidazol-5-¡l)-1H-p¡razol-4-¡l]-benzo[b] tiofen-2-il-metanona;(248) [5-amino-1- (2-meti-1H-bendmidazol-5-l) -1H-p¡razol-4-¡l] -benzo [b] thiophene-2-yl-methanone ;
(249) [5-amino-1-(2-met¡l-1H-bendmidazol-5-¡l)-1H-p¡razol-4-¡l]-benzot¡azol-2-¡l-metanona;(249) [5-amino-1- (2-methyl-1H-bendmidazol-5-α) -1 H -pyrazol-4-α] -benzotholzol-2-l-methanone;
(250) [5-amino-1-(2-met¡l-1H-bendmidazol-5-¡l)-1H-p¡razol-4-¡l]-(4-fluoro-fen¡l)-metanona;(250) [5-amino-1- (2-meti-1H-bendmidazol-5-l) -1 H -pyrazol-4-l] - (4-fluoro-phenol) -methanone ;
(251) [5-am¡no-1-(2-met¡l-1H-bendmidazol-5-¡l)-1H-p¡razol-4-¡l]-(3-cloro-fen¡l)-metanona;(251) [5-am-1-1 (2-methyl-1H-bendmidazol-5-l) -1 H-p.razole-4-l] - (3-chloro-phenol) -metanone;
(252) [5-amino-1-(2-met¡l-1H-bendmidazol-5-¡l)-1H-p¡razol-4-¡l]-qu¡nol¡n-3-¡l-metanona;(252) [5-Amino-1- (2-Methyl-1H-Bendmidazol-5-L) -1H-Pyrol-4-L] -qunolnol-3-L- methanone;
(253) [5-am¡no-1-(2-met¡l-1H-bendm¡dazol-5-il)-1H-p¡razol-4-¡l]-qu¡nol¡n-7-¡l-metanona; y(253) [5-am-1-1 (2-met-1-1-blessmdazol-5-yl) -1 H-p.razole-4-l] -qunol-n-7- L-methanone; Y
(254) [5-amino-1-(2-met¡l-1H-bendmidazol-5-¡l)-1H-p¡razol-4-¡l]-qu¡nol¡n-6-¡l-metanona.(254) [5-Amino-1- (2-Methyl-1H-Bendmidazol-5-L) -1H-Pyrol-4-L] -qunolnol-6-L- methanone
[6] Una composición farmacéutica que comprende el compuesto de uno cualquiera de [1] a [5], o una sal farmacéuticamente aceptable del mismo; y un portador.[6] A pharmaceutical composition comprising the compound of any one of [1] to [5], or a pharmaceutically acceptable salt thereof; and a carrier.
[7] (no reivindicado) Un agente para la inhibición de la actividad del FGFR, que comprende como un ingrediente activo, el compuesto de uno cualquiera de [1] a [5], o una sal farmacéuticamente aceptable del mismo.[7] (not claimed) An agent for the inhibition of FGFR activity, comprising as an active ingredient, the compound of any one of [1] to [5], or a pharmaceutically acceptable salt thereof.
[8] Un agente para uso en un método de prevención o tratamiento del cáncer, que comprende como un ingrediente activo el compuesto de uno cualquiera de [1] a [5], o una sal farmacéuticamente aceptable del mismo.[8] An agent for use in a cancer prevention or treatment method, which comprises as an active ingredient the compound of any one of [1] to [5], or a pharmaceutically acceptable salt thereof.
[9] El agente para prevenir o tratar el cáncer de [8], en donde el cáncer es al menos uno seleccionado del grupo que consiste en: cáncer de mama, leucemia mielocítica aguda, cáncer de páncreas, cáncer de vejiga, cáncer de próstata, cáncer de esófago, angiogénesis, cáncer de estómago, cáncer de cuerpo uterino, cáncer de ovario, tumor cerebral, cáncer de colon, mieloma múltiple, hepatocarcinoma, cáncer pulmonar, y cáncer de tiroides.[9] The agent to prevent or treat cancer of [8], wherein the cancer is at least one selected from the group consisting of: breast cancer, acute myelocytic leukemia, pancreas cancer, bladder cancer, prostate cancer , esophageal cancer, angiogenesis, stomach cancer, uterine body cancer, ovarian cancer, brain tumor, colon cancer, multiple myeloma, hepatocarcinoma, lung cancer, and thyroid cancer.
5 [10] Una composición que comprende el compuesto o sal farmacéuticamente aceptable del mismo de uno cualquiera[10] A composition comprising the compound or pharmaceutically acceptable salt thereof of any one
de [1] a [5] para uso en un método para prevenir o tratar el cáncer, que comprende administrar una cantidad farmacéuticamente efectiva de dicha composición a un paciente en necesidad de prevención o tratamiento del cáncer.from [1] to [5] for use in a method for preventing or treating cancer, which comprises administering a pharmaceutically effective amount of said composition to a patient in need of prevention or treatment of cancer.
[11] Uso del compuesto de uno cualquiera de [1] a [5] o una sal farmacéuticamente aceptable del mismo en la 10 producción de un agente para prevenir o tratar el cáncer.[11] Use of the compound of any one of [1] to [5] or a pharmaceutically acceptable salt thereof in the production of an agent to prevent or treat cancer.
[12] El compuesto de uno cualquiera de [1] a [5] o una sal farmacéuticamente aceptable del mismo, para uso en un método para prevenir o tratar el cáncer.[12] The compound of any one of [1] to [5] or a pharmaceutically acceptable salt thereof, for use in a method to prevent or treat cancer.
La presente descripción o invención, respectivamente, también incluye lo siguiente.The present description or invention, respectively, also includes the following.
[101] Un compuesto representado por la siguiente fórmula (I) general, o una sal farmacéuticamente aceptable del 15 mismo:[101] A compound represented by the following general formula (I), or a pharmaceutically acceptable salt thereof:
(n(n
en donde R-i, R2, R3, y R4 cada uno representa independientemente el grupo enumerado a continuación:where R-i, R2, R3, and R4 each independently represent the group listed below:
R1 representa hidrógeno, hidroxi, halógeno, ciano, nitro, haloalquilo C1.4, alquilo Ci.6, alquenilo C2-6, alquinilo C2-6, arilo C6.io alquilo C 1.4, -OR5, -NR6R7, -(CR8R9)nZi, -C(0)NRi2Ri3, -SR14, -SOR15, -SO2R16, -NRi7S02Ri8, COOH, arilo 20 C6-io que es opcionalmente sustituido por uno o más grupos seleccionados del grupo P, heteroarilo de 5- a 10- miembros o heterociclilo de 3- a 10- miembros que es opcionalmente sustituido por uno o más grupos seleccionados del grupo Q, -COR19, -COOR20, -0C(0)R2i, -NR22C(0)R23, -NR24C(S)R25, -C(S)NR26R27, -SO2NR28R29, -OSO2R30, - SO3R31, o -Si(R32)3;R1 represents hydrogen, hydroxy, halogen, cyano, nitro, C1.4 haloalkyl, Ci.6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6 aryl.io C 1.4 alkyl, -OR5, -NR6R7, - (CR8R9) nZi, -C (0) NRi2Ri3, -SR14, -SOR15, -SO2R16, -NRi7S02Ri8, COOH, aryl 20 C6-io which is optionally substituted by one or more groups selected from the P group, 5- to 10-membered heteroaryl or 3- to 10-membered heterocyclyl which is optionally substituted by one or more groups selected from the group Q, -COR19, -COOR20, -0C (0) R2i, -NR22C (0) R23, -NR24C (S) R25, -C (S) NR26R27, -SO2NR28R29, -OSO2R30, - SO3R31, or -Si (R32) 3;
R2 representa hidrógeno, hidroxi, halógeno, ciano, nitro, haloalquilo C1-4, alquilo C-i-e, alquenilo C2-6, alquinilo C2.6, 25 arilo C6-io alquilo C1.4, -OR5, -NRsR7, -(CRsRgJnZ-,, -C(0)NRi2Ri3, -SR14, -SOR15, -S02Ri6, -NRi7S02Ri8, COOH, arilo C6-10 que es opcionalmente sustituido por uno o más grupos seleccionados del grupo P, heteroarilo de 5- a 10- mlembros o heterociclilo de 3- a 10- miembros que es opcionalmente sustituido por uno o más grupos seleccionados del grupo Q, -COR19, -COOR20, -OC(0)R2i, -NR22C(0)R23, -NR24C(S)R25, -C(S)NR26R27, -S02NR28R2g, -OSO2R30, - SO3R31, o- Si(R32)3; oR2 represents hydrogen, hydroxy, halogen, cyano, nitro, C1-4 haloalkyl, Cie alkyl, C2-6 alkenyl, C2.6 alkynyl, C6 aryl-io C1.4 alkyl, -OR5, -NRsR7, - (CRsRgJnZ- ,, -C (0) NRi2Ri3, -SR14, -SOR15, -S02Ri6, -NRi7S02Ri8, COOH, C6-10 aryl which is optionally substituted by one or more groups selected from the P group, 5- to 10-membered heteroaryl or 3- to 10-membered heterocyclyl which is optionally substituted by one or more groups selected from the group Q, -COR19, -COOR20, -OC (0) R2i, -NR22C (0) R23, -NR24C (S) R25, - C (S) NR26R27, -S02NR28R2g, -OSO2R30, - SO3R31, or- Si (R32) 3; or
30 R1 y R2, junto con un átomo unido al mismo, forman un heterociclilo de 3- a 10- miembros o heteroarilo de 5- a 10- miembros, en donde el heterociclilo o heteroarilo es opcionalmente sustituido por un halógeno;R1 and R2, together with an atom attached thereto, form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl, wherein the heterocyclyl or heteroaryl is optionally substituted by a halogen;
R3 representa hidrógeno, alquilo C1-5, arilo C6-io alquilo C1-6, o haloalquilo C1.4;R3 represents hydrogen, C1-5 alkyl, C6-aryl-C1-6 alkyl, or C1.4 haloalkyl;
R4 representa hidrógeno, halógeno, alquilo C1-3, haloalquilo C-m, hidroxi, ciano, nitro, alcoxi C1-4, -(CH2)nZi, -NR8R7, - ORs, -C(0)NRi2R13, -SR14, -SOR15, -S02Rie, NRi7S02Ri8, COOH, -CORig, -COOR20, -0C(0)R2i, -NR22C(0)R23, - 35 NR24C(S)R25, -C(S)NR26R27i -S02NR28R29, -OS02R3o-S03R3i, o -Si(R32)3lR4 represents hydrogen, halogen, C1-3 alkyl, haloalkyl Cm, hydroxy, cyano, nitro, C1-4 alkoxy, - (CH2) nZi, -NR8R7, - ORs, -C (0) NRi2R13, -SR14, -SOR15, -S02Rie, NRi7S02Ri8, COOH, -CORig, -COOR20, -0C (0) R2i, -NR22C (0) R23, - 35 NR24C (S) R25, -C (S) NR26R27i -S02NR28R29, -OS02R3o-S03R3i, or -Yes (R32) 3l
A representa indol o plrrolA represents indole or plrrol
55
1010
15fifteen
20twenty
2525
3030
3535
4040
45Four. Five
Rs representa alquilo C1-5, cicloalqullo C3-7, clcloalqullo C3-7 alquilo C1-3, alquenilo C2-6, alqulnllo C2-6, haloalquilo C1-4, alcoxl C1-3 alquilo C2-4, alcoxi C1-3 alcoxl C2-4 alquilo C2-4, amlnoalquilo C2-4, alqullamlno C1.4 alquilo C2-4, dl(alquilo Ci- 4)amlno alquilo C2-4, arilo C6-io, arilo Ce-io alquilo C1.3, o heterociclilo de 3- a 10- miembros alquilo C1.3, heterociclilo de 3- a 10- miembros, heteroarilo de 5- a 10- miembros, heteroarilo de 5- a 10- miembros alquilo C1.3, monohidroxl alquilo C1-6, dihidroxi alquilo Ci.6, o trihidroxi alquilo C1.6 que es opcionalmente sustituido por uno o más grupos seleccionados del grupo Q;Rs represents C1-5 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl C1-3 alkyl, C2-6 alkenyl, C2-6 alkenyl, C1-4 haloalkyl, C1-3 alkoxy C1-3 alkyl, C1-3 alkoxy alkoxy C2-4 C2-4alkyl, C2-4alkylalkyl, C1.4alkyllamineC2-4alkyl, dl (C1-4alkyl) amylC2-4alkyl, C6-io aryl, Ceyl-C1-aryl-aryl, or 3- to 10-membered heterocyclyl C1.3 alkyl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl C1.3 alkyl, monohydroxl C1-6 alkyl, dihydroxy C1.6 alkyl, or trihydroxy C1.6 alkyl which is optionally substituted by one or more groups selected from group Q;
R6 y R7, que son iguales o diferentes, cada uno representa hidrógeno, alquilo Ci_4, alquenilo C2-6, alqulnllo C2.6, haloalquilo C1.4, alcoxi C1.3 alquilo C2.4, arilo C6-10 alquilo C1.3, heterociclilo de 3- a 10- miembros alquilo C1.3, heteroarilo de 5- a 10- miembros alquilo C1.3, monohidroxl alquilo C2-6, dihidroxi alquilo C2-6, trihidroxi alquilo C2-6, heterociclilo de 3- a 10- miembros, amlnoalquilo C2-4, alqullamlno C1.4 alquilo C2-4, di(alquilo Ci-4)amino alquilo C2-4, o clano(alquilo C1.3); o R6 y R7, junto con un átomo de nitrógeno unido al mismo, forman un heterociclilo de 3- a 10- mlembros o heteroarilo de 5- a 10- miembros;R6 and R7, which are the same or different, each represents hydrogen, C1-4 alkyl, C2-6 alkenyl, C2.6 alkyl, C1.4 haloalkyl, C1.3 alkoxyC2.4 alkyl, C6-10 aryl C1.3 alkyl , 3- to 10-membered heterocyclyl C1.3 alkyl, 5- to 10-membered heteroaryl C1.3 alkyl, monohydroxy C2-6 alkyl, dihydroxy C2-6 alkyl, trihydroxy C2-6 alkyl, heterocyclyl 3- to 10- members, C2-4alkylalkyl, C1.4alkyllamineC2-4alkyl, di (C1-4alkyl) aminoC2-4alkyl, or clano (C1.3alkyl); or R6 and R7, together with a nitrogen atom attached thereto, form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl;
n representa 1 a 3;n represents 1 to 3;
Rs y R9, que son iguales o diferentes, cada uno representa hidrógeno, alquilo C1.4, o halógeno; o alternativamente, Rs y R9, junto con un átomo de carbono unido al mismo, forman un anillo cicloalifático; Z1 representa hidrógeno, NR10R11, hidroxilo, o heterociclilo de 3- a 10- miembros o heteroarilo de 5- a 10- miembros que es opclonalmente sustituido por uno o más grupos independientemente seleccionados del grupo Q;Rs and R9, which are the same or different, each represents hydrogen, C1.4 alkyl, or halogen; or alternatively, Rs and R9, together with a carbon atom attached thereto, form a cycloaliphatic ring; Z1 represents hydrogen, NR10R11, hydroxyl, or 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl which is opclonally substituted by one or more groups independently selected from group Q;
R10 y R11, que son iguales o diferentes, cada uno representa alquilo C1.4, alquenilo C2-6, alqulnllo C2-6, haloalquilo C-i. 4, alcoxl C1-3 alquilo C2-4, ciano(alqullo C1-3), o alquilsulfonilo C1-3 alquilo C2-4; o alternativamente, R-ioy R11, junto con un átomo de nitrógeno unido al mismo, forman un heterociclilo de 3- a 10- miembros o heteroarilo de 5- a 10- mlembros;R10 and R11, which are the same or different, each represents C1.4 alkyl, C2-6 alkenyl, C2-6 alkyl, C-i haloalkyl. 4, C1-3alkoxyC2-4alkyl, cyano (C1-3alkyl), or C1-3alkylsulfonylC2-4alkyl; or alternatively, R-io and R11, together with a nitrogen atom attached thereto, form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl;
R12 y R13, que son iguales o diferentes, cada uno representa hidrógeno, alquilo C1-4, alquenilo C2-6, alquinilo C2-6, haloalquilo C-m, alcoxi C1-3 alquilo C2-4, arilo C6-10, heteroarilo de 5- a 10- miembros, heterociclilo de 3- a 10- miembros, arilo C6-10 alquilo C-m, heterociclilo de 3- a 10- miembros alquilo C1.3, heteroarilo de 5- a 10- miembros alquilo C1-3, ciano(alquilo C1.3), alquilsulfonilo C1-3 alquilo C2-4, anillo cicloalifático de 3- a 10- miembros, heteroarilo de 5- a 10- miembros, o heterociclilo de 3- a 10- miembros; o alternativamente, R12 y R13, junto con un átomo de nitrógeno unido al mismo, forman un heterociclilo de 3- a 10- miembros o heteroarilo de 5- a 10- miembros que es opcionalmente sustituido por uno o más grupos seleccionados del grupo Q;R12 and R13, which are the same or different, each represents hydrogen, C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cm haloalkyl, C1-3 alkoxyC2-4 alkyl, C6-10 aryl, heteroaryl of 5 - 10-membered, 3- to 10-membered heterocyclyl, C6-10 aryl alkyl Cm, 3- to 10-membered heterocyclyl C1.3 alkyl, 5- to 10-membered heteroaryl C1-3 alkyl, cyano ( C1.3 alkyl), C1-3 alkyl sulfonyl C2-4 alkyl, 3- to 10-membered cycloaliphatic ring, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl; or alternatively, R12 and R13, together with a nitrogen atom attached thereto, form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl which is optionally substituted by one or more groups selected from group Q;
R14 representa alquilo C1.4, alquenilo C2-6, alquinilo C2-6, haloalquilo Cm, arilo Ce-io que es opcionalmente sustituido por uno o más grupos seleccionados del grupo P, o heteroarilo de 5- a 10- miembros o heterociclilo de 3- a 10- miembros que es opcionalmente sustituido por uno o más grupos seleccionados del grupo Q;R14 represents C1.4 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cm haloalkyl, Ce-io aryl which is optionally substituted by one or more groups selected from the P group, or 5- to 10-membered heteroaryl or heterocyclyl of 3- to 10-members that is optionally substituted by one or more groups selected from group Q;
R15 representa alquilo Cm, alquenilo C2-e, alquinilo C2.e, haloalquilo Cm, arilo C6-io que es opcionalmente sustituido por uno o más grupos seleccionados del grupo P, o heteroarilo de 5- a 10- miembros o heterociclilo de 3- a 10- miembros que es opclonalmente sustituido por uno o más grupos seleccionados del grupo Q;R 15 represents C 1 -C alkyl, C 2 -alkenyl, C 2 alkynyl, C 1 -alkyl alkyl, C 6 -aryl aryl which is optionally substituted by one or more groups selected from the P group, or 5- to 10-membered heteroaryl or 3- to 3- 10-members who are opclonally substituted by one or more groups selected from group Q;
R16 representa alquilo Cm, alquenilo C2-6, alqulnllo C2-6, haloalquilo Cm, arilo Ce-io que es opcionalmente sustituido por uno o más grupos seleccionados del grupo P, o heteroarilo de 5- a 10- miembros o heterociclilo de 3- a 10- miembros que es opclonalmente sustituido por uno o más grupos seleccionados del grupo Q;R16 represents C 1 -C 6 alkyl, C 2-6 alkenyl, C 2-6 alkyl, C 1 -alkyl alkyl which is optionally substituted by one or more groups selected from the P group, or 5- to 10-membered heteroaryl or 3- to 3-heterocyclyl 10-members who are opclonally substituted by one or more groups selected from group Q;
R17 representa hidrógeno o alquilo Cm;R17 represents hydrogen or Cm alkyl;
R18 representa alquilo Cm, alquenilo C2-6, alqulnllo C2-6, haloalquilo Cm, arilo Ce-io que es opclonalmente sustituido por uno o más grupos seleccionados del grupo P, o heteroarilo de 5- a 10- miembros o heterociclilo de 3- a 10- mlembros que es opcionalmente sustituido por un(os) grupo(s) seleccionado(s) del grupo Q;R18 represents C2-6 alkyl, C2-6 alkenyl, C2-6 alkenyl, C1-aryl haloalkyl which is opclonally substituted by one or more groups selected from the P group, or 5- to 10-membered heteroaryl or 3- to 3- heterocyclyl at 10-members that is optionally substituted by a group (s) selected from group Q;
R19 representa hidrógeno, alquilo Cm, clcloalqullo C3.7, haloalquilo Cm, arilo Ce-io, o heteroarilo de 5- a 10- mlembros o heterociclilo de 3- a 10- miembros que es opcionalmente sustituido por uno o más grupos seleccionados del grupo Q;R19 represents hydrogen, Cm alkyl, C3.7 cycloalkyl, Cm haloalkyl, Ce-io aryl, or 5- to 10-membered heteroaryl or 3- to 10-membered heterocyclyl which is optionally substituted by one or more groups selected from the group Q;
R20 representa alquilo Cm, cicloalqullo C3.7, haloalquilo Cm, arilo C6-io, heteroarilo de 5- a 10- miembros, o heterociclilo de 3- a 10- miembros;R20 represents Cm alkyl, C3.7 cycloalkyl, Cm haloalkyl, C6-io aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl;
R21 representa alquilo Cm, cicloalquilo C3.7, haloalquilo Cm, arilo C6-io, heteroarilo de 5- a 10- miembros, o heterociclilo de 3- a 10- miembros;R21 represents Cm alkyl, C3.7 cycloalkyl, Cm haloalkyl, C6-io aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl;
R22 representa hidrógeno, alquilo Cm, o haloalquilo Cm;R22 represents hydrogen, Cm alkyl, or Haloalkyl Cm;
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R23 representa hidrógeno, alquilo C1.4, cicloalquilo C3-7, haloalquilo C1-4, arilo Ce-io, heteroarilo de 5- a 10- miembros, o heterociclilo de 3- a 10-miembros;R23 represents hydrogen, C1.4 alkyl, C3-7 cycloalkyl, C1-4 haloalkyl, Ce-io aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl;
R24 representa hidrógeno, alquilo Ci_4, o haloalquilo Ci_4;R24 represents hydrogen, C1-4 alkyl, or C1-4 haloalkyl;
R25 representa alquilo Ci_4, cicloalquilo C3.7, haloalquilo Ci_4, arilo Ce-io, heteroarilo de 5- a 10- miembros, o heterociclilo de 3- a 10- miembros;R25 represents C 1-4 alkyl, C 3-7 cycloalkyl, C 1-4 haloalkyl, Ce-io aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl;
R26 y R27, que son iguales o diferentes, cada uno representa hidrógeno, alquilo Ci_4, alquenilo C2-6, alquinilo C2-6, haloalquilo Ci_4, alcoxilo Ci_3 alquilo C2.4, arilo C6-io, heteroarilo de 5- a 10- miembros, heterociclilo de 3- a 10- miembros, arilo C6-io alquilo Ci_4, heterociclilo de 3- a 10- miembros alquilo C1.3, heteroarilo de 5- a 10- miembros alquilo C1-3, ciano(alquilo C1.3), alquilsulfonilo C1.3 alquilo C2.4, o anillo cicloalifático de 3- a 10- miembros; o alternativamente, R26 y R27, junto con un átomo de nitrógeno unido al mismo, forman un heterociclilo de 3- a 10- miembros o heteroarilo de 5- a 10- miembros;R26 and R27, which are the same or different, each represents hydrogen, Ci_4 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ci_4 haloalkyl, Ci_3 alkoxy C2.4 alkyl, C6-io aryl, heteroaryl 5- to 10- members, 3- to 10-membered heterocyclyl, C6-aryl-Ci_4 alkyl, 3- to 10-membered heterocyclyl C1.3 alkyl, 5- to 10-membered heteroaryl C1-3 alkyl, cyano (C1.3 alkyl ), C1.3 alkylsulfonyl C2.4 alkyl, or 3- to 10-membered cycloaliphatic ring; or alternatively, R26 and R27, together with a nitrogen atom attached thereto, form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl;
R28 y R29, que son iguales o diferentes, cada uno representa hidrógeno, alquilo Ci_4, alquenilo C2-6, alquinilo C2.6, haloalquilo Ci_4, alcoxilo C1.3 alquilo C2.4, arilo C6-10, heteroarilo de 5- a 10- miembros, heterociclilo de 3- a 10- miembros, arilo Ce-io alquilo Ci_4, heterociclilo de 3- a 10- miembros alquilo C1.3, heteroarilo de 5- a 10- miembros alquilo C1.3, ciano(alquilo C1.3), alquilsulfonilo C1.3 alquilo C2.4, o anillo cicloalifático de 3- a 10- miembros; o alternativamente, R28 y R2g, junto con un átomo de nitrógeno unido al mismo, forman un heterociclilo de 3- a 10- miembros o heteroarilo de 5- a 10- miembros;R28 and R29, which are the same or different, each represents hydrogen, Ci_4 alkyl, C2-6 alkenyl, C2.6 alkynyl, Ci_4 haloalkyl, C1.3 alkoxy C2.4 alkyl, C6-10 aryl, 5- to heteroaryl 10- members, 3- to 10-membered heterocyclyl, Ce-io Ci_4 alkyl, 3- to 10-membered heterocyclyl C1.3 alkyl, 5- to 10-membered heteroaryl C1.3 alkyl, cyano (C1 alkyl .3), C1.3 alkylsulfonyl C2.4 alkyl, or 3- to 10-membered cycloaliphatic ring; or alternatively, R28 and R2g, together with a nitrogen atom attached thereto, form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl;
R30 representa alquilo C-|.4, cicloalquilo C3.7, haloalquilo Ci_4, arilo Ce-io, heteroarilo de 5- a 10- miembros, o heterociclilo de 3- a 10- miembros;R30 represents C- | .4 alkyl, C3.7 cycloalkyl, Ci_4 haloalkyl, Ce-io aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl;
R31 representa alquilo Ci_4, cicloalquilo C3.7, haloalquilo C1 _4, arilo Ce-io, heteroarilo de 5- a 10- miembros, o heterociclilo de 3- a 10- miembros;R31 represents Ci_4 alkyl, C3.7 cycloalkyl, C1_4 haloalkyl, Ce-io aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl;
R32 representa alquilo Ci_4 o arilo Ce-io;R32 represents Ci_4 alkyl or Ce-io aryl;
<grupo P><group P>
hidrógeno, halógeno, alquilo Ci_4, haloalquilo C1.4, -OH, alcoxi C1.3, heterociclilamino de 3- a 10- miembros, -S02Ri6, -CN, -N02, y heterociclilo de 3- a 10- miembros;hydrogen, halogen, Ci_4 alkyl, C1.4 haloalkyl, -OH, C1.3 alkoxy, 3- to 10-membered heterocyclylamino, -S02Ri6, -CN, -N02, and 3- to 10-membered heterocyclyl;
<grupo Q><group Q>
hidrógeno, halógeno, alquilo C1.4, haloalquilo C1.4, -OH, alcoxi Ci_3, heterociclilamina de 3- a 10- miembros, -S02Ri6, -CN, -N02, cicloalquilo C3.7, -COR19, y heterociclilo de 3- a 10- miembros.hydrogen, halogen, C1.4 alkyl, C1.4 haloalkyl, -OH, Ci_3 alkoxy, 3- to 10-membered heterocyclylamine, -S02Ri6, -CN, -N02, C3.7 cycloalkyl, -COR19, and 3-heterocyclyl - 10-members.
De acuerdo con la invención, en el punto [101] descrito anteriormente,According to the invention, in the point [101] described above,
R4 representa hidrógeno, halógeno, alquilo C1.3, perfluoroalquilo C1.3, ciano, metanosulfonilo, hidroxilo, alcoxi, o amino;R4 represents hydrogen, halogen, C1.3 alkyl, perfluoroalkyl C1.3, cyano, methanesulfonyl, hydroxyl, alkoxy, or amino;
A representa indol o pirrol;A represents indole or pyrrole;
el citado compuesto representado por la fórmula (I) general no incluye la [5-amino-1-(2-metil-1H-bencimidazol-5-il)- 1H-pirazol-4-il]-[5-(4-trifluorometil-fenil)-1H-indol-2-il]-metanona; y cicloalquilo se refiere a un grupo hidrocarburo alifático monovalente cíclico saturado o parcialmente saturado.the said compound represented by the general formula (I) does not include [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [5- (4- trifluoromethyl-phenyl) -1H-indole-2-yl] -methanone; and cycloalkyl refers to a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group.
[102] (no reivindicado) El compuesto de [101] o una sal farmacéuticamente aceptable del mismo, en donde A representa azaindol.[102] (not claimed) The compound of [101] or a pharmaceutically acceptable salt thereof, wherein A represents azaindole.
[103] El compuesto de [101] o [102], o una sal farmacéuticamente aceptable del mismo, en donde R3 representa hidrógeno, alquilo C1.4, arilo Ce-io alquilo C1.4, o perfluoroalquilo C1.3.[103] The compound of [101] or [102], or a pharmaceutically acceptable salt thereof, wherein R3 represents hydrogen, C1.4 alkyl, aryl Ce-io C1.4 alkyl, or perfluoroalkyl C1.3.
[104] El compuesto de uno cualquiera de [101] a [103], o una sal farmacéuticamente aceptable del mismo, en donde R4 representa hidrógeno, halógeno, alquilo 61.3, perfluoroalquilo C1.3, ciano, metanosulfonilo, hidroxilo, alcoxi, o amino.[104] The compound of any one of [101] to [103], or a pharmaceutically acceptable salt thereof, wherein R4 represents hydrogen, halogen, alkyl 61.3, perfluoroalkyl C1.3, cyano, methanesulfonyl, hydroxyl, alkoxy, or Not me.
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[105] El compuesto de [101] o una sal farmacéuticamente aceptable del mismo, que se selecciona del grupo que consiste en:[105] The compound of [101] or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of:
(1) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-p¡razol-4-¡l]-(1H-¡ndol-2-¡l)-metanona;(1) [5-am-1-1 (2-methyl-1H-benzyldazol-5-yl) -1H-p'razole-4-l] - (1H-landol- 2-¡) -methanone;
(2) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-¡l]-(6-pirrolidin-1 -ilmetil-1 H-ind ol-2-il)-metanona;(2) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-α] - (6-pyrrolidin-1-ylmethyl-1 H-ind ol -2-yl) -methanone;
(3) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-(4-hidroxi-p¡peridin-1 -ilmetil)-1 H-indol-2-il]-metanona;(3) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6- (4-hydroxy-pperidin-1-methylmethyl) ) -1 H-indole-2-yl] -methanone;
(4) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-(1H-p¡rrolo[3,2-c]p¡r¡d¡n-2-¡l)-metanona;(4) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1H-pyrazol-4-l] - (1H-pyrol [ 3,2-c] p¡r¡d¡n-2-l) -methanone;
(5) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-p¡razol-4-¡l]-(6-p¡peraz¡n-1-¡lmet¡l-1 H-¡nd ol-2-il)-metanona;(5) [5-am-1-1 (2-methyl-1H-benzyldazol-5-yl) -1 H-p.razole-4-l] - (6-p. Peraz ¡N-1-¡lmet¡l-1 H-¡ol-2-yl) -methanone;
(6) [5-am¡no-1-(2-met¡l-1H-bencim¡dazol-5-¡l)-1H-p¡razol-4-¡l]-[6-(2-morfol¡n-4-¡l-etox¡)-1 H-¡ndol-2-il]-metanona;(6) [5-am-1-1 (2-methyl-1H-benzimdazol-5-l) -1 H-p.razol-4-l] - [6- (2-morphol ¡N-4-¡l-ethox¡) -1 H-¡ndol-2-yl] -methanone;
(7) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-(tetrahidro-piran-4-¡loxi)-1 H-indol-2-il]-metanona;(7) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6- (tetrahydro-pyran-4-loxy) -1 H-indol-2-yl] -methanone;
(8) [5-am¡no-1-(2-met¡l-1H-benc¡midazol-5-¡l)-1H-p¡razol-4-¡l]-(4-cloro-1H-¡ndol-2-¡l)-metanona;(8) [5-am-n-1- (2-methyl-1H-benzylmidazol-5-l) -1H-p¡razol-4-l] - (4-chloro-1H- Ndol-2-¡l) -methanone;
(9) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-p¡razol-4-¡l]-(5-bromo-1H-¡ndol-2-¡l)-metanona;(9) [5-am-1-1 (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-l] - (5-bromo-1H -¡Ndol-2-¡l) -methanone;
(10) [5-am¡no-1-(2-met¡l-1H-bencim¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(4-yodo-1H-¡ndol-2-¡l)-metanona;(10) [5-am-1-1 (2-methyl-1H-benzimdazol-5-l) -1H-p.razole-4-l] - (4-iodine-1H- Ndol-2-¡l) -methanone;
(11) 2-[5-am¡no-1-(2-met¡l-1H-bencim¡dazol-5-¡l)-1H-p¡razol-4-carbon¡l]-1H-¡ndol-5-carbon¡tr¡lo;(11) 2- [5-am-no-1- (2-methyl-1H-benzimdadazol-5-l) -1H-p¡razol-4-carbonl] -1H-landol -5-carbon¡tr¡lo;
(12) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-p¡razol-4-¡l]-(6-bromo-5-fluoro-1H-¡ndol-2-il)-metanona;(12) [5-am-no-1- (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-l] - (6-bromo-5 -fluoro-1H-¡ndol-2-yl) -methanone;
(13) [5-amlno-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-¡l]-(5-et¡n¡l-1H-¡ndol-2-¡l)-metanona;(13) [5-amlno-1- (2-methyl-1H-benzyldazol-5-yl) -1H-pyrazol-4-ll] - (5-et¡n¡l-1H -¡Ndol-2-¡l) -methanone;
(14) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-il]-[6-(2-fluoro-fenil)-1H-indol-2 -il]-metanona;(14) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1H-prazol-4-yl] - [6- (2- fluoro-phenyl) -1H-indole-2-yl] -methanone;
(15) [5-amino-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-il]-[6-(3-fluoro-fenil)-1H-indol-2 -il]-metanona;(15) [5-amino-1- (2-methyl-1H-benzyldazol-5-l) -1H-prazol-4-yl] - [6- (3-fluoro-phenyl) -1H-indole-2-yl] -methanone;
(16) [5-amino-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-il]-[6-(4-fluoro-fenil)-1H-indol-2 -il]-metanona;(16) [5-Amino-1- (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-yl] - [6- (4-fluoro-phenyl) -1H-indole-2-yl] -methanone;
(17) [5-amino-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-il]-[6-(2-cloro-fenil)-1H-indol-2 -il]-metanona;(17) [5-amino-1- (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-yl] - [6- (2-chloro-phenyl) -1H-indole-2-yl] -methanone;
(18) [5-amino-1-(2-metil-1H-bencim¡dazol-5-¡l)-1H-p¡razol-4-il]-[6-(3-cloro-fenil)-1H-indol-2 -il]-metanona;(18) [5-amino-1- (2-methyl-1H-benzimdazol-5-l) -1H-p¡razol-4-yl] - [6- (3-chloro-phenyl) -1H -indole-2-yl] -methanone;
(19) [5-amino-1-(2-metil-1-bencimidazol-5-¡l)-1H-p¡razol-4-il]-[6-(4-cloro-fenil)-1H-indol-2 -il]-metanona;(19) [5-amino-1- (2-methyl-1-benzimidazol-5-l) -1H-p¡razol-4-yl] - [6- (4-chloro-phenyl) -1H-indole -2-yl] -methanone;
(20) [5-amino-1-(2-metil-1H-bencim¡dazol-5-¡l)-1H-p¡razol-4-il]-[6-(2-trifluorometil-fenil)-1 H-indol-2-il]-metanona;(20) [5-Amino-1- (2-methyl-1H-benzimdadazol-5-α) -1 H -pyrazol-4-yl] - [6- (2-trifluoromethyl-phenyl) -1 H-indol-2-yl] -methanone;
(21) [5-amino-1-(2-metil-1H-bencim¡dazol-5-¡l)-1H-p¡razol-4-il]-[6-(3-trifluorometil-fenil)-1 H-indol-2-il]-metanona;(21) [5-amino-1- (2-methyl-1H-benzimdadazol-5-α) -1H-p¡razol-4-yl] - [6- (3-trifluoromethyl-phenyl) -1 H-indol-2-yl] -methanone;
(22) [5-amino-1-(2-metil-1H-bencimidazol-5-¡l)-1H-p¡razol-4-il]-[6-(4-trifluorometil-fenil)-1 H-indol-2-il]-metanona;(22) [5-Amino-1- (2-methyl-1H-benzimidazol-5-1) -1H-p¡razol-4-yl] - [6- (4-trifluoromethyl-phenyl) -1 H- indole-2-yl] -methanone;
(23) [5-amino-1-(2-metil-1H-bencimidazol-5-¡l)-1H-p¡razol-4-il]-(4-bromo-1H-indol-2-il)-metanona;(23) [5-amino-1- (2-methyl-1H-benzimidazol-5-l) -1H-p¡razol-4-yl] - (4-bromo-1H-indole-2-yl) - methanone;
(24) [5-amino-1-(2-metil-1H-bencimidazol-5-¡l)-1H-p¡razol-4-il]-[6-(3-fluoro-piridin-2-il)-1H-in dol-2-il]-metanona;(24) [5-amino-1- (2-methyl-1H-benzimidazol-5-l) -1H-p¡razol-4-yl] - [6- (3-fluoro-pyridin-2-yl) -1H-in dol-2-yl] -methanone;
(25) [5-amino-1-(2-metil-1H-bencimidazol-5-¡l)-1H-p¡razol-4-il]-(6-metil-1H-indol-2-il)-metanona;(25) [5-amino-1- (2-methyl-1H-benzimidazol-5-l) -1H-p¡razol-4-yl] - (6-methyl-1H-indole-2-yl) - methanone;
(26) [5-amino-1-(2-metil-1H-bencimidazol-5-¡l)-1H-pirazol-4-il]-[5-(4,4-difluoro-piperid¡na-1-carbonil)-1H-¡ndol- 2-¡l]- metanona;(26) [5-amino-1- (2-methyl-1 H -benzimidazol-5-1) -1 H -pyrazol-4-yl] - [5- (4,4-difluoro-piperidine-1- carbonyl) -1H-¡ndol- 2-¡l] - methanone;
(27) [5-amino-1-(2-metil-1H-bencimidazol-5-¡l)-1H-p¡razol-4-¡l]-[5-(3,3-difluoro-piperid¡na-1-carbonil)-1H-¡ndol- 2-¡l]- metanona;(27) [5-amino-1- (2-methyl-1H-benzimidazol-5-l) -1H-p¡razol-4-¡] - [5- (3,3-difluoro-piperidine) -1-carbonyl) -1H-¡ndol- 2-¡l] - methanone;
(28) (2,2,2-trifluoro- etil)-amida del ácido 2-[5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-carbonil]-1H-indol- 5-carboxílico;(28) 2- [5-Amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-carbonyl] - (2,2,2-trifluoro-ethyl) -amide 1H-indole-5-carboxylic;
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(29) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-¡l]-[6-(5-trifluorometil-piridin-2-il)-1H-¡ndol-2-¡l]-metanona;(29) [5-am-1-1 (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-l] - [6- (5-trifluoromethyl- pyridin-2-yl) -1H-¡ndol-2-¡l] -methanone;
(30) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-¡l]-[6-(6-trifluorometil-piridin-2-il)-1H-indol-2-¡l]-metanona;(30) [5-am-1-1 (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-l] - [6- (6-trifluoromethyl- pyridin-2-yl) -1H-indole-2-l] -methanone;
(31) [5-am¡no-1-(2-met¡l-1 H-benc¡m¡dazol-5-il)-1 H-pirazol-4-¡l]-[6-(5-cloro-piridin-2-il)-1 H-in dol-2-¡l]-metanona;(31) [5-am-1-1 (2-methyl-1 H-benzyldazol-5-yl) -1 H-pyrazol-4-l] - [6- (5- chloro-pyridin-2-yl) -1 H-in dol-2-1] -methanone;
(32) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-¡l]-[6-(4-metil-piridin-2-il)-1H-indol-2-il]-metanona;(32) [5-am-1-1 (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-l] - [6- (4-methyl- pyridin-2-yl) -1H-indole-2-yl] -methanone;
(33) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-¡l]-[6-(3-cloro-4-fluoro-fenil)-1 H-indol-2-¡l]-metanona;(33) [5-am-1-1 (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-l] - [6- (3-chloro- 4-fluoro-phenyl) -1 H-indole-2-l] -methanone;
(34) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-¡l]-[6-(3-trifluorometil-piridin-2-il)-1H-indol-2-¡l]-metanona;(34) [5-amine-1- (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-l] - [6- (3-trifluoromethyl- pyridin-2-yl) -1H-indole-2-l] -methanone;
(35) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-[6-(4-trifluorometil-piridin-2-il)-1H-indol-2-¡l]-metanona;(35) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-l] - [6- (4-trifluoromethyl -pyridin-2-yl) -1H-indole-2-l] -methanone;
(36) [5-am¡no-1-(6-fluoro-2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-il]-(1H-indol-2-il)-metanona;(36) [5-am-no-1- (6-fluoro-2-methyl-1H-benzyldazol-5-l) -1H-prazol-4-yl] - (1H -indole-2-yl) -methanone;
(37) ácido 2-[5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-carbonil]-1H-indol-6-carboxílico;(37) 2- [5-Amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-carbonyl] -1 H -indole-6-carboxylic acid;
(38) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(6-hidroximetil-1H-indol-2-il)-metanona;(38) [5-Amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (6-hydroxymethyl-1 H -indole-2-yl) -methanone;
(39) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-{6-[2-(4-metil-piperazin-1-il)-etoxi]-1H-indol- 2-il}-(39) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - {6- [2- (4-methyl-piperazin-1-yl) -ethoxy] -1H-indole-2-yl} -
metanona;methanone;
(40) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(3-metil-oxetan-3-ilmetoxi)-1H-indol-2-il]-metanona;(40) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [6- (3-methyl-oxetan-3-ylmethoxy) -1H- indole-2-yl] -methanone;
(41) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(3-fluoro-piperidin-1-ilmetil)-1H-indol-2-il]-metanona;(41) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [6- (3-fluoro-piperidin-1-ylmethyl) -1H- indole-2-yl] -methanone;
(42) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(6-{[bis(2-metoxi-etil)amino ]-metil}-1H-indol- 2-il)- metanona;(42) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (6 - {[bis (2-methoxy-ethyl) amino] -methyl } -1H-indole-2-yl) -methanone;
(43) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-{6-[(metil-prop-2-inil-amino) metil]-1H-indol- 2-il}-(43) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - {6 - [(methyl-prop-2-inyl-amino) methyl] -1H-indole-2-yl} -
metanona;methanone;
(44) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(3,3-difluoro-pirrolidin-1-il metil)-1H-indol- 2-il]-(44) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6- (3,3-difluoro-pyrrolidin-1-yl methyl) -1H-indole-2-il] -
metanona;methanone;
(45) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(2,5-dimetil-pirrolidin-1-il metil)-1H-indol- 2-il]-(45) [5-Amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6- (2,5-dimethyl-pyrrolidin-1-yl methyl) -1H-indole-2-il] -
metanona;methanone;
(46) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(3,3-difluoro-piperidin-1-ilmetil)-1H-indol- 2-il]-(46) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6- (3,3-difluoro-piperidin-1-ylmethyl) - 1H-indole-2-yl] -
metanona;methanone;
(47) [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-((S)-3-metil-morfolin-4-il metil)-1 H-indol- 2-il]-(47) [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6 - ((S) -3-methyl-morpholin-4 -yl methyl) -1 H-indole-2-yl] -
metanona;methanone;
(48) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(6-bromo-1H-indol-2-il)-metanona;(48) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (6-bromo-1 H -indole-2-yl) -methanone;
(49) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5-yodo-1H-indol-2-il)-metanona;(49) [5-Amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (5-iodo-1 H -indole-2-yl) -methanone;
(50) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(1H-pirrolo[3,2-b]piridin-2-il)-metanona;(50) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (1 H -pyrrolo [3,2-b] pyridin-2-yl) -metanone;
(51) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5-bromo-6-trifluorometil-1H-indol-2-il)-metanona;(51) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (5-bromo-6-trifluoromethyl-1H-indole-2-yl) -metanone;
(52) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(6-yodo-1H-indol-2-il)-metanona;(52) [5-Amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (6-iodo-1 H -indole-2-yl) -methanone;
(53) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(4-metil-1H-indol-2-il)-metanona;(53) [5-Amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (4-methyl-1 H -indole-2-yl) -methanone;
(54) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(4-isopropil-1H-indol-2-il)-metanona;(54) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (4-isopropyl-1 H -indole-2-yl) -methanone;
(55) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[5-(2-fluoro-fenil)-1H-indol-2 -il]-metanona;(55) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [5- (2-fluoro-phenyl) -1H-indole-2 - il] -methanone;
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(56) [5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-(5-benc¡l-1H-¡ndol-2-il)-metanona;(56) [5-amino-1- (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-l] - (5-benzyl-1H- Ndol-2-yl) -methanone;
(57) [5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-[5-(2-tr¡fluoromet¡l-fenil)-1 H-¡ndol-2-¡l]-metanona;(57) [5-amino-1- (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-l] - [5- (2-trfluoromet ¡L-phenyl) -1 H-¡ndol-2-¡l-methanone;
(58) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-[5-(3-fluorofen¡l)-1H-indol-2-il]-metanona;(58) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-l] - [5- (3-fluorophen L) -1H-indole-2-yl] -methanone;
(59) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-[5-(3-tr¡fluoromet¡l-fenil)-1 H-indol-2-¡l]-metanona;(59) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1H-pyrazol-4-l] - [5- (3-tr Fluoromethyl-phenyl) -1 H-indol-2-l] -methanone;
(60) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-(4-et¡n¡l-1H-¡ndol-2-¡l)-metanona;(60) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-l] - (4-et¡n) l-1H-¡ndol-2-¡l) -methanone;
(61) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-(5H-[1,3]d¡oxolo[4,5-f]indol-6-il)-metanona;(61) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1H-pyrazol-4-l] - (5H- [1,3 ] deoxolo [4,5-f] indole-6-yl) -methanone;
(62) [5-am¡no-1-(7-fluoro-2-met¡l-1H-benc¡m¡dazol-5-il)-1H-p¡razol-4-¡l]-(1H-¡ndol-2-¡l)-metanona;(62) [5-am-no-1- (7-fluoro-2-methyl-1H-benzyldazol-5-yl) -1 H-prazol-4-l] - (1 H -¡Ndol-2-¡l) -methanone;
(63) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-[5-(4-tr¡fluoromet¡l-fenil)-1 H-indol-2-¡l]-metanona;(63) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1H-pyrazol-4-l] - [5- (4-tr Fluoromethyl-phenyl) -1 H-indol-2-l] -methanone;
(64) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-(5-butox¡-1H-¡ndol-2-¡l)-metanona;(64) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1H-pyrazol-4-l] - (5-butoxy-1H -¡Ndol-2-¡l) -methanone;
(65) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-[5-(1-met¡l-p¡per¡d¡n-4-il)-1H -indol-2-¡l]-metanona;(65) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1H-pyrazol-4-l] - [5- (1-met Lp¡per¡d¡n-4-il) -1H-indol-2-¡l] -methanone;
(66) N-{2-[5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-carbon¡l]-1H-¡ndol-6-il}-metanosulfonam¡da;(66) N- {2- [5-amino-1- (2-methyl-1H-benzyldazol-5-l) -1H-pyrazol-4-carbonl] -1H-¡ ndol-6-yl} -methanesulfonamide;
(67) [5-am¡no-1-(2-met¡l-1H-bendm¡dazol-5-¡l)-1H-pirazol-4-¡l]-[6-(6-morfol¡n-4-¡l-p¡r¡d¡n-3-il)-1H-indol-2-il]-metanona;(67) [5-am-1-1 (2-met-1-1-blessmdazol-5-1) -1 H -pyrazol-4-1] - [6- (6-morphol] -4-¡lp¡r¡d¡n-3-il) -1H-indol-2-il] -methanone;
(68) [5-am¡no-1-(2-met¡l-1H-bendm¡dazol-5-¡l)-1H-pirazol-4-¡l]-(6-but¡l-1H-¡ndol-2-¡l)-metanona;(68) [5-am-1-1 (2-methyl-1H-blessmdazol-5-l) -1 H -pyrazol-4-l] - (6-butyl-1H- Ndol-2-¡l) -methanone;
(69) [5-am¡no-1-(2-metil-1H-bendm¡dazol-5-¡l)-1H-p¡razol-4-¡l]-[6-(1-met¡l-1H-p¡razol-4-¡l)-1H-indol-2-il]-metanona;(69) [5-am-no-1- (2-methyl-1H-bendm¡dazol-5-¡l) -1H-p¡razol-4-¡] - [6- (1-methyl) -1H-p¡razol-4-¡1) -1H-indole-2-yl] -methanone;
(70) [5-am¡no-1-(2-metil-1H-bendm¡dazol-5-¡l)-1H-p¡razol-4-¡l]-[6-(5-metox¡-p¡r¡d¡n-3-¡l)-1H -indol-2-il]-metanona;(70) [5-am-no-1- (2-methyl-1H-bendm¡dazol-5-¡l) -1H-p¡razol-4-¡l] - [6- (5-methox¡- p¡r¡d¡n-3-¡l) -1 H -indole-2-yl] -methanone;
(71) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-il]-[6-(2-metoxi-piridin-3-il)-1H -indol-2-¡l]-metanona;(71) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-yl] - [6- (2-methoxy) pyridin-3-yl) -1 H -indole-2-l] -methanone;
(72) [5-am¡no-1-(2-met¡l-1H-benc¡midazol-5-¡l)-1H-p¡razol-4-il]-(6-ddopropil-1H-indol-2-il)-metanona;(72) [5-am-1-1 (2-methyl-1H-benzylmidazol-5-l) -1H-p¡razol-4-yl] - (6-ddopropyl-1H-indole -2-yl) -methanone;
(73) [5-am¡no-1-(2-met¡l-1H-bencim¡dazol-5-¡l)-1H-p¡razol-4-il]-[6-(2-metoxi-fenil)-1H-indo 1-2-il]-metanona;(73) [5-am-1-1 (2-methyl-1H-benzimdazol-5-yl) -1 H -pyrazol-4-yl] - [6- (2-methoxy) phenyl) -1H-indo 1-2-yl] -methanone;
(74) [5-am¡no-1-(2-met¡l-1H-benc¡midazol-5-¡l)-1H-p¡razol-4-il]-(6-fenil-1H-indol-2-il)-metanona;(74) [5-amine-1- (2-methyl-1H-benzimidazol-5-l) -1H-p¡razol-4-yl] - (6-phenyl-1H-indole -2-yl) -methanone;
(75) [5-am¡no-1-(2-met¡l-1H-bendm¡dazol-5-il)-1H-pirazol-4-il]-[6-(5-metanosulfonilo-piridin-3 -il)-1H-¡ndol-2-¡l]- metanona;(75) [5-amine-1- (2-methyl-1H-bendmdadazol-5-yl) -1 H -pyrazol-4-yl] - [6- (5-methanesulfonyl-pyridin-3 -il) -1H-¡ndol-2-¡l] - methanone;
(76) [5-am¡no-1-(2-met¡l-1H-benc¡midazol-5-¡l)-1H-p¡razol-4-il]-(6-isopropil-1H-indol-2-il)-metanona;(76) [5-amine-1- (2-methyl-1H-benzylmidazol-5-l) -1H-p¡razol-4-yl] - (6-isopropyl-1H-indole -2-yl) -methanone;
(77) [5-am¡no-1-(2-met¡l-1H-bendm¡dazol-5-¡l)-1H-pirazol-4-il]-(6-piridin-2-il-1H-indol-2-il)-metanona;(77) [5-am-1-1 (2-methyl-1H-blessmdazol-5-l) -1 H -pyrazol-4-yl] - (6-pyridin-2-yl-1H -indole-2-yl) -methanone;
(78) [5-am¡no-1-(2-met¡l-1H-benc¡midazol-5-il)-1H-pirazol-4-il]-(5-dclopropil-1H-¡ndol-2-il)-metanona;(78) [5-am-1-1 (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (5-dclopropyl-1 H-landol-2 -il) -methanone;
(79) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-il]-(6-piridazin-3-il-1H-indol-2-il) -metanona;(79) [5-amine-1- (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-yl] - (6-pyridazin-3-yl- 1H-indole-2-yl) -methanone;
(80) [5-am¡no-1-(2-met¡l-1H-bendmidazol-5-il)-1H-pirazol-4-il]-(5-isopropoxi-1H-¡ndol-2-il)-metanona;(80) [5-am-1-1 (2-methyl-1H-bendmidazol-5-yl) -1 H -pyrazol-4-yl] - (5-isopropoxy-1 H-dino-2-yl ) -methanone;
(81) [5-amino-1-(2-metil-1H-bendmidazol-5-il)-1H-pirazol-4-il]-[5-(2-metoxi-etox¡)-1H-indo 1-2-il]-metanona;(81) [5-amino-1- (2-methyl-1H-bendmidazol-5-yl) -1H-pyrazol-4-yl] - [5- (2-methoxy-ethoxy) -1H-indo 1- 2-yl] -methanone;
(82) [5-amino-1-(2-met¡l-1H-bendmidazol-5-il)-1H-pirazol-4-il]-(5-dclopropilmetox¡-1H-indo l-2-il)-metanona;(82) [5-amino-1- (2-methyl-1H-bendmidazol-5-yl) -1 H -pyrazol-4-yl] - (5-dclopropylmethox-1H-indo l-2-yl) -metanone;
(83) [5-am¡no-1-(2-met¡l-1H-bendmidazol-5-il)-1H-pirazol-4-il]-(2,2-difluoro-5H-[1,3]d¡oxolo[4, 5-f]indol-6-il)-metanona;(83) [5-am-1-1 (2-methyl-1 H-bendmidazol-5-yl) -1 H -pyrazol-4-yl] - (2,2-difluoro-5 H- [1,3 ] deoxolo [4,5-f] indole-6-yl) -methanone;
(84) [5-am¡no-1-(2-met¡l-1H-bendmidazol-5-il)-1H-pirazol-4-il]-[6-(3-doro-p¡r¡d¡n-2-¡l)-1H-in dol-2-il]-metanona;(84) [5-am-1-1 (2-methyl-1H-bendmidazol-5-yl) -1 H -pyrazol-4-yl] - [6- (3-doro-p¡r¡d ¡N-2-¡l) -1H-in dol-2-il] -methanone;
(85) [5-am¡no-1-(2-met¡l-1H-bendmidazol-5-il)-1H-pirazol-4-il]-[6-(5-fluoro-p¡r¡d¡n-2-¡l)-1H-¡n dol-2-il]-metanona;(85) [5-am-1-1 (2-methyl-1H-bendmidazol-5-yl) -1 H -pyrazol-4-yl] - [6- (5-fluoro-p¡r¡d ¡N-2-¡l) -1H-¡n dol-2-il] -methanone;
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(86) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-(6-morfolin-4-il-pi ridazin-3-il)-1 H-indol-2-il]- metanona;(86) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6- (6-morpholin-4-yl-pi ridazin- 3-yl) -1 H-indol-2-yl] - methanone;
(87) [5-am¡no-1-(2-met¡l-1H-bencim¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(5-cloro-6-c¡cloprop¡lmetox¡-1H-¡ndol-2-¡l)-metanona;(87) [5-am-1-1 (2-methyl-1H-benzimdazol-5-l) -1 H-p.razol-4-l] - (5-chloro-6- ccloclopropylmethox-1H-¡ndol-2-l) -methanone;
(88) [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-M]-[6-(2,4-difluoro-fenil)-1 H-ind ol-2-il]-metanona;(88) [5-Amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-M] - [6- (2,4-difluoro-phenyl) -1 H -ind ol-2-yl] -methanone;
(89) [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-(6-p¡ridaz¡n-4-il-1 H-¡ndol-2-il) -metanona;(89) [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - (6-pridaz-4-yl-1 H -¡Ndol-2-yl) -methanone;
(90) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-p¡razol-4-¡l]-(3-fluoro-1H-¡ndol-2-¡l)-metanona;(90) [5-am-1-1 (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-l] - (3-fluoro-1H -¡Ndol-2-¡l) -methanone;
(91) [5-amino-1 -(2-metil-1 H-benc¡midazol-5-il)-1 H-pirazol-4-il]-[5-(1 -isopropil-piper¡din-4-il)-6-tr¡fluoromet¡l1 H-¡ndol-2- ¡l]-metanona;(91) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [5- (1-isopropyl-piperine-4 -il) -6-trfluoromethyl1 H-¡-ndol-2-1] -methanone;
(92) 2-[5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-carbon¡l]-1H-¡ndol-6-carbonitrilo;(92) 2- [5-Amino-1- (2-methyl-1H-benzyldazol-5-l) -1H-pyrolol-4-carbonl] -1H-landol -6-carbonitrile;
(93) [5-amino-1 -(2-metil-1 H-benc¡ midazol-5-il)-1 H-pirazol-4-il]-[5-(1,2,3,6-tetrahidro-pirid¡n-4-il)-1 H-indol-2-il]-(93) [5-amino-1 - (2-methyl-1 H-benzyl midazol-5-yl) -1 H -pyrazol-4-yl] - [5- (1,2,3,6-tetrahydro -pyridin-4-yl) -1 H-indol-2-yl] -
metanona;methanone;
(94) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-(5-piperidin-4-¡l-1 H-indol-2-il) -metanona;(94) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (5-piperidin-4-¡-1 H-indole- 2-yl) -methanone;
(95) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[5-((R)-3-fluoro-pirrol¡din-1 -il met¡l)-1H-¡ndol- 2-¡l]- metanona;(95) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [5 - ((R) -3-fluoro-pyrrolidin -1-methl) -1H-¡ndol- 2-¡] - methanone;
(96) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-p¡razol-4-¡l]-(6-fluoro-5-p¡per¡d¡n-4-¡l-1H-in dol-2-¡l)-metanona;(96) [5-am-1-1 (2-methyl-1H-benzyldazol-5-yl) -1 H-p.razole-4-l] - (6-fluoro-5 -p¡per¡d¡n-4-¡l-1H-in dol-2-¡l) -methanone;
(97) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-M]-[6-fluoro-5-(1-metil-piperid¡n-4-il)-1 H-¡ndol-2-il]- metanona;(97) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-M] - [6-fluoro-5- (1-methyl-piperidine) -4-yl) -1 H-α-2-yl] - methanone;
(98) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-[5-(1-isoprop¡l-p¡per¡d¡n-4-¡l)-1H-indol-2-il]-metanona;(98) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H-p.razol-4-l] - [5- (1 -isoprop¡lp¡per¡d¡n-4-¡l) -1H-indole-2-yl] -methanone;
(99) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-p¡razol-4-il]-[6-fluoro-5-(1 -isopropil-piperid in-4-il)-1 H-indol- 2-il]- metanona;(99) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 Hp¡razol-4-yl] - [6-fluoro-5- (1-isopropyl-piperid in- 4-yl) -1 H-indol-2-yl] -methanone;
(100) [5-am¡no-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-(6-piridin-3-il-1 H-indol-2-il)-metanona;(100) [5-amine-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (6-pyridin-3-yl-1 H-indole -2-yl) -methanone;
(101) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-M]-[5-(6-morfolin-4-ilpiridin-3-il)-1 H-indol-2-il]-metanona;(101) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-M] - [5- (6-morpholin-4-ylpyridin-3-yl ) -1 H-indole-2-yl] -methanone;
(102) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-(5-pirid¡n-3-il-1 H-indol-2-il)-metanona;(102) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (5-pyridine-3-yl-1 H-indole -2-yl) -methanone;
(103) [5-am¡ no-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[5-(6-piperazin-1 -il-piridin-3-il)-1 H-indol-2-il]- metanona;(103) [5-am¡ no-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [5- (6-piperazin-1-yl-pyridin) -3-yl) -1 H-indol-2-yl] -methanone;
(104) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[5-(6-hidroxi-p¡rid¡n-3-il)-1 H-indol-2-il]-metanona;(104) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [5- (6-hydroxy-pridrid-3 -il) -1 H-indol-2-yl] -methanone;
(105) [5-amino-1 -(2-metil-1 H-benc¡midazol-5-il)-1 H-pirazol-4-il]-[6-fluoro-5-(4-metil-piperazin-1 -ilmetil)-1 H-indol- 2-il]- metanona;(105) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6-fluoro-5- (4-methyl-piperazin -1-methylmethyl) -1 H-indole-2-yl] -methanone;
(106) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-(6-fluoro-5-pirrolidin-1 -ilmetil-1 H-indol-2-il)-metanona;(106) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (6-fluoro-5-pyrrolidin-1-ylmethyl-1 H -indole-2-yl) -methanone;
(107) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-( 1 -metil-piperidin-4-il)-1 H -indol-2-il]-metanona;(107) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6- (1-methyl-piperidin-4-yl) - 1 H -indole-2-yl] -methanone;
(108) [5-am¡no-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-(4-morfolin-4-M-fenil)-1 H-indol-2-il]-metanona;(108) [5-amine-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6- (4-morpholin-4-M-phenyl ) -1 H-indole-2-yl] -methanone;
(109) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-(3,4,5,6-tetrahidro-2H-[1,2’] b¡p¡r¡din-5’-M)- 1 H-indol- 2-¡l]-metanona;(109) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6- (3,4,5,6-tetrahydro-2H - [1,2 '] b¡p¡r¡din-5'-M) - 1 H-indole-2-¡] -methanone;
(110) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-¡l]-[6-(6-piperazin-1 -il-piridin-3-il)-1 H-indol-2-il]- metanona;(110) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-¡] - [6- (6-piperazin-1-yl-pyridin- 3-yl) -1 H-indol-2-yl] - methanone;
(111) [5-am¡no-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[5-(6-metoxi-p¡rid¡n-3-il)-1 H -indol-2-il]-metanona;(111) [5-am-1-(2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [5- (6-methoxy-pridrid) -3-yl) -1 H -indole-2-yl] -methanone;
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(112) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-p¡razol-4-¡l]-[5-((S)-3-met¡l-morfol¡n-4-¡l met¡l)-1 H-indol- 2-¡l]- metanona;(112) [5-am-1-1 (2-methyl-1H-benzyldazol-5-yl) -1 H-p.razol-4-l] - [5 - ((S ) -3-met-1-morphol-4-1-methyl) -1 H-indole-2-1] - methanone;
(113) [5-am¡ no-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-((R)-3-fluoro-pirrolidin-1 -il metil)-1 H-indol- 2-il]- metanona;(113) [5-am¡ no-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6 - ((R) -3-fluoro-pyrrolidin -1-methyl] -1 H-indole-2-yl] -methanone;
(114) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pi razol-4-il]-[5-(2,5-dimet¡l-p¡rrolidin-1 -il metil)-1 H-indol- 2-il]- metanona;(114) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pi razol-4-yl] - [5- (2,5-dimetl-lp¡rrolidin- 1-methyl] -1 H-indole-2-yl] -methanone;
(115) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[5-(3-fluoro-pi peridin-1 -ilmetil)-1 H-indol-2-il]- metanona;(115) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [5- (3-fluoro-pi peridin-1-methylmethyl) -1 H-indole-2-yl] - methanone;
(116) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pi razol-4-il]-[5-(3,3-difluoro-piperidi n-1 -ilmetil)-1 H-indol- 2-il]- metanona;(116) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pi razol-4-yl] - [5- (3,3-difluoro-piperidi n-1 -ylmethyl) -1 H-indole-2-yl] -methanone;
(117) [5-amino-1 -(2-metil-1 H-benc¡midazol-5-il)-1 H-pirazol-4-il]-{6-[2-(4-metil-piperaz¡n-1 -il) piridin-4-il]-1 H-indol- 2-il}- metanona;(117) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - {6- [2- (4-methyl-piperaz) n-1-yl) pyridin-4-yl] -1 H-indol-2-yl} -methanone;
(118) [5-am¡no-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-(6-piridin-4-il-1 H-indol-2-il)-metanona;(118) [5-amine-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (6-pyridin-4-yl-1 H-indole -2-yl) -methanone;
(119) [5-amino-1 -(2-metil-1 H-benc¡ midazol-5-il)-1 H-pirazol-4-il]-[5-(4-fluoropiper¡din-1 -ilmetil )-1 H-indol-2-il]-(119) [5-amino-1 - (2-methyl-1 H-benzyl midazol-5-yl) -1 H -pyrazol-4-yl] - [5- (4-fluoropiper¡din-1-ylmethyl ) -1 H-indole-2-yl] -
metanona;methanone;
(120) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pi razol-4-il]-[5-(4,4-difluoro-piperid¡ n-1 -ilmetil)-1 H-indol- 2-il]- metanona;(120) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pi razol-4-yl] - [5- (4,4-difluoro-piperid¡ n- 1-methylmethyl) -1 H-indol-2-yl] -methanone;
(121) [5-ami no-1 -(2-difluorometil-1 H-benc¡ midazol-5-il)-1 H-pi razol-4-il]-[5-( 1 -metil-piperidin-4 -il)-1 H-indol-2-il]-(121) [5-ami no-1 - (2-difluoromethyl-1 H-benzyl midazol-5-yl) -1 H-pi razol-4-yl] - [5- (1-methyl-piperidin-4 -il) -1 H-indole-2-yl] -
metanona;methanone;
(122) [5-am¡no-1-(2-d¡fluoromet¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(1H-¡ndol-2-¡l)-metanona;(122) [5-am¡no-1- (2-d¡fluoromet¡l-1H-benc¡m¡dazol-5-¡l) -1H-p¡razol-4-¡l] - (1H- Ndol-2-¡l) -methanone;
(123) [5-am¡no-1-(2-met¡l-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[5-(3,3-d¡fluoro-pirrol¡din-1-¡l metil)-1 H-in dol-2-il]- metanona;(123) [5-amine-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [5- (3,3-dfluoro -pyrrolin-1-methyl) -1 H-in dol-2-yl] - methanone;
(124) [5-am¡no-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-¡l]-[5-(1-ciclopent¡l-p¡per¡d¡n-4-il )-1H-indol-2-il]-(124) [5-am¡no-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-¡] - [5- (1-cyclopent¡lp¡per¡d¡ n-4-il) -1H-indole-2-il] -
metanona;methanone;
(125) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[5-(1-c¡clohexil-piperid¡n-4-¡l) -1H-¡ndol-2-¡l]-metanona;(125) [5-amine-1- (2-methyl-1H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [5- (1-c-cyclohexyl-piperidine) -4-¡l) -1H-¡ndol-2-¡l] -methanone;
(126) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(4-bromo-1H-pirrol-2-il)-metanona;(126) [5-amine-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (4-bromo-1 H -pyrrole-2-yl) -metanone;
(127) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(1H-p¡rrol-2-¡l)-metanona;(127) [5-amine-1- (2-methyl-1H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (1 H -pyrrol-2-l) - methanone;
(128) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(4-fenil-1H-p¡rrol-2-¡l)-metanona;(128) [5-amine-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (4-phenyl-1H-pyrrol-2- L) -methanone;
(129) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[4-(3-cloro-fenil)-1H-pirrol-2-il]-metanona;(129) [5-amine-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [4- (3-chloro-phenyl) -1 H- pyrrol-2-yl] -methanone;
(130) [5-am¡no-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[4-(4-fluoro-fenil)-1 H-pirrol-2-il]-metanona;(130) [5-amine-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [4- (4-fluoro-phenyl) -1 H -pyrrol-2-yl] -methanone;
(131) [5-am¡no-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[4-(3-fluoro-fenil)-1 H-pirrol-2-il]-metanona;(131) [5-amine-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [4- (3-fluoro-phenyl) -1 H -pyrrol-2-yl] -methanone;
(132) [5-am¡no-1-(2-met¡l-1H-benc¡midazol-5-¡l)-1H-p¡razol-4-¡l]-(6-morfol¡n-4-ilmet¡l-1H-¡n dol-2-il)-metanona;(132) [5-am-1-1 (2-methyl-1H-benzylmidazole-5-l) -1H-p.razole-4-l] - (6-morphol- 4-ilmet¡l-1H-¡n dol-2-il) -methanone;
(133) [5-am¡no-1-(2-met¡l-1H-benc¡midazol-5-il)-1H-pirazol-4-¡l]-[4-(2-morfol¡n-4-¡l-et¡lam¡n o)-1H-¡ndol-2-¡l]-metanona;(133) [5-amine-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-l] - [4- (2-morphol- 4-¡l-et¡lam¡no) -1H-¡ndol-2-¡l] -methanone;
(134) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-p¡razol-4-il]-[5-(4-met¡l-piperazina-1-carbon¡l)-1 H-indol- 2-il]- metanona;(134) [5-amine-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H-prazol-4-yl] - [5- (4-methyl-piperazine -1-carbonl) -1 H-indole-2-yl] -methanone;
(135) [5-am¡no-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-(2-morfolin-4-il-etilamino)-1 H-¡ndol-2-il]-metanona;(135) [5-amine-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6- (2-morpholin-4-yl-ethylamino ) -1 H-¡-ol-2-yl] -methanone;
(136) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[5-(piperazina-1-carbonil)-1H-indol-2-il]-metanona;(136) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [5- (piperazine-1-carbonyl) -1H-indole-2- il] -methanone;
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(137) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[4-(2-metox¡-et¡lam¡no)-1H-indol-2-il]-metanona;(137) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [4- (2-methox¡-et¡lam¡no) -1H -indole-2-yl] -methanone;
(138) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-p¡razol-4-il]-[4-(2-hidrox¡-1-h¡drox¡metil -etilamino)- 1H-indol-2-¡l]- metanona;(138) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-p¡razol-4-yl] - [4- (2-hydrox¡-1-h¡drox¡ methyl-ethylamino) -1H-indole-2-1] -methanone;
(139) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[4-(2-piridin-4-¡l-et¡lam¡no)-1H-indol-2-il]-metanona;(139) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [4- (2-pyridin-4-¡-l-et¡lam¡ no) -1H-indole-2-yl] -methanone;
(140) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(2-metoxi-et¡lam¡no)-1H-indol-2-¡l]-metanona;(140) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [6- (2-methoxy-et allamine) -1H- indole-2-l] -methanone;
(141) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(6-morfolin-4-¡l-1H-¡ndol-2-il)-metanona;(141) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (6-morpholin-4-¡-1H-¡ndol-2- il) -methanone;
(142) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(4-morfolin-4-¡l-1H-¡ndol-2-¡l)-metanona;;(142) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (4-morpholin-4-¡-1H-¡-dol-2- L) -metanone ;;
(143) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(4-morfolin-4-¡lmet¡l-1H-¡n dol-2-¡l)-metanona;(143) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (4-morpholin-4-lmet¡l-1H-¡n dol -2-¡) -methanone;
(144) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5-morfolin-4-ilmet¡l-1H-¡n dol-2-¡l)-metanona;(144) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (5-morpholin-4-ylmet¡l-1H-¡n dol- 2-¡) -methanone;
(145) [5-amino-1-(2-metil-1H-benc¡midazol-5-il)-1H-pirazol-4-il]-[5-(morfolina-4-carbon¡l)-1H-¡ndol-2-¡l]-metanona;(145) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [5- (morpholine-4-carbonl) -1H- Ndol-2-¡l] -methanone;
(146) [5-am¡no-1-(2-¡soprop¡l-1H-bencimidazol-5-il)-1H-p¡razol-4-il]-(1H-indol-2-il)-metanona;(146) [5-amno-1- (2-sopropyl-1H-benzimidazol-5-yl) -1H-p¡razol-4-yl] - (1H-indole-2-yl) - methanone;
(147) [5-am¡no-1-(2-prop¡l-1H-benc¡m¡dazol-5-il)-1H-p¡razol-4-il]-(1H-indol-2-il)-metanona;(147) [5-amine-1- (2-propyl-1H-benzyldazol-5-yl) -1H-p¡razol-4-yl] - (1H-indole-2- il) -methanone;
(148) [5-am¡no-1-(1H-benc¡midazol-5-¡l)-1H-pirazol-4-¡l]-(1H-indol-2-il)-metanona;(148) [5-amine-1- (1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (1 H -indole-2-yl) -methanone;
(149) [5-am¡no-1-(2-tr¡fluoromet¡l-1H-bencim¡dazol-5-¡l)-1H-pirazol-4-il]-(1H-indol-2-il)-metanona;(149) [5-am-n-1- (2-trfluoromethyl-1H-benzimdazol-5-l) -1H-pyrazol-4-yl] - (1H-indole-2-yl ) -methanone;
(150) [5-am¡no-1-(2-et¡l-1H-benc¡midazol-5-il)-1H-pirazol-4-¡l]-(1H-indol-2-il)-metanona;(150) [5-am-1-1 (2-et-l-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-1] - (1 H-indole-2-yl) - methanone;
(151) [5-amino-1 -(2-bencil-1 H-benc¡m¡dazol-5-¡l)-1 H-pirazol-4-il]-( 1 H-¡ndol-2-¡l)-metanona;(151) [5-amino-1 - (2-benzyl-1 H-benzimdazol-5-l) -1 H-pyrazol-4-yl] - (1 H-¡-ndol-2-¡ l) -methanone;
(152) 1-(4-{2-[5-amino-l-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-p¡razol-4-carbon¡l]-1H-¡ndol-5-¡lmet¡l}-p¡peraz¡n- 1-¡l)-(152) 1- (4- {2- [5-amino-l- (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-carbonl] -1H-¡ndol-5-¡lmet¡l} -p¡peraz¡n- 1-¡l) -
etanona;ethanone;
(153) [5-amino-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-[5-(4-metanosulfon¡lo-p¡peraz¡n -1-¡lmetil)- 1H-indol-2- ¡l]-metanona;(153) [5-amino-1- (2-methyl-1H-benzyldazol-5-l) -1H-p¡razol-4-l] - [5- (4-methanesulfonyl) -p¡peraz¡n -1-lmethyl) - 1H-indole-2- 1] -methanone;
(154) [5-amino-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(5-piperazin-1-ilmetil-1H-¡nd ol-2-il)-metanona;(154) [5-amino-1- (2-methyl-1H-benzimdazol-5-l) -1H-p¡razol-4-l] - (5-piperazin-1-ylmethyl- 1H-¡ol-2-yl) -methanone;
(155) 1-(4-{2-[5-amino-l-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-carbonil]-1H-indol-6-ilmetil}piperaz¡n- 1-¡l)-(155) 1- (4- {2- [5-amino-l- (2-methyl-1H-benzyldazol-5-l) -1H-pyrazol-4-carbonyl] -1H- indole-6-ylmethyl} piperazine- 1-l) -
etanona;ethanone;
(156) [5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-il]-[6-(4-metil-piperazin-1-ilmet¡l)-1H-¡ndol-2-¡l]- metanona;(156) [5-amino-1- (2-methyl-1H-benzyldazol-5-l) -1H-pyrazol-4-yl] - [6- (4-methyl-piperazin- 1-ilmet¡l) -1H-¡ndol-2-¡l] - methanone;
(157) [5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-[5-(4-met¡l-p¡peraz¡n-1-¡lmet¡l)-1H-indol-2-il]- metanona;(157) [5-amino-1- (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-l] - [5- (4-metl) Peraz¡n-1-lmet¡l) -1H-indole-2-yl] - methanone;
(158) [5-amino-1-(2-metil-1 H-benc¡m¡dazol-5-il)-1 H-p¡razol-4-il]-(5-pirrolidin-1 -ilmetil-1 H-ind ol-2-il)-metanona;(158) [5-Amino-1- (2-methyl-1 H-benzyldazol-5-yl) -1 Hp.razol-4-yl] - (5-pyrrolidin-1-ylmethyl-1 H -ind ol-2-yl) -methanone;
(159) [5-amino-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(4-fluoro-1H-¡ndol-2-¡l)-metanona;(159) [5-amino-1- (2-methyl-1H-benzimdazol-5-l) -1H-p¡razol-4-l] - (4-fluoro-1H-landol -2-¡) -methanone;
(160) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-il]-(5-fluoro-1H-¡ndol-2-¡l)-metanona;(160) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-yl] - (5-fluoro-1H -¡Ndol-2-¡l) -methanone;
(161) [5-amino-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(6-fluoro-1H-¡ndol-2-¡l)-metanona;(161) [5-Amino-1- (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-l] - (6-fluoro-1 H-diene) -2-¡) -methanone;
(162) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-p¡razol-4-il]-(1 H-pirrolo[2,3-b]piridin-2-il)-metanona;(162) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 Hp.razole-4-yl] - (1 H -pyrrolo [2,3-b] pyridin-2 -il) -methanone;
(163) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-il]-(5-fluoro-6-morfolin-4-ilmetil-1H-indol-2-¡l)-metanona;(163) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1H-pyrazol-4-yl] - (5-fluoro-6-morpholin -4-ylmethyl-1H-indole-2-l) -methanone;
(164) 2-[5-amino-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-carbonil]-1H-indol-5-carboxílico ácido;(164) 2- [5-Amino-1- (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-carbonyl] -1 H -indole-5-carboxylic acid ;
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(165) [5-am¡no-1-(2-met¡l-1H-bencim¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(5-metox¡-1H-¡ndol-2-¡l)-metanona;(165) [5-am-1-1 (2-methyl-1H-benzimdazol-5-l) -1H-p.razole-4-l] - (5-methox-1H -¡Ndol-2-¡l) -methanone;
(166) [5-am¡no-1-(2-met¡l-1H-bencim¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(4,6-d¡metox¡-1H-indol-2-il)-metanona;(166) [5-am-1-1 (2-methyl-1H-benzimdazol-5-l) -1H-p.razole-4-l] - (4,6-d¡ methox-1H-indole-2-yl) -methanone;
(167) [5-amino-1-(2-met¡l-1H-bencimidazol-5-il)-1H-p¡razol-4-il]-(4-metoxi-1H-indol-2-¡l)-metanona;(167) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (4-methoxy-1H-indole-2-l) ) -methanone;
(168) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-p¡razol-4-il]-(6-metoxi-1H-indol-2-¡l)-metanona;(168) [5-amine-1- (2-methyl-1H-benzimidazol-5-yl) -1H-prazol-4-yl] - (6-methoxy-1H-indole-2- L) -methanone;
(169) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-p¡razol-4-il]-(4,6-d¡metil-1H-indol-2-¡l)-metanona;(169) [5-amine-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H-prazol-4-yl] - (4,6-d-methyl-1 H- indole-2-l) -methanone;
(170) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-p¡razol-4-il]-(5-fe/í-butil-1H-indol-2-¡l)-metanona;(170) [5-am-1-1 (2-methyl-1H-benzimidazol-5-yl) -1 H-prazol-4-yl] - (5-fe / í-butyl-1 H- indole-2-l) -methanone;
(171) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-p¡razol-4-il]-(5-¡sopropil-1H-¡ndol-2-¡l)-metanona;(171) [5-amine-1- (2-methyl-1H-benzimidazol-5-yl) -1H-p¡razol-4-yl] - (5-sopropyl-1H-landol- 2-¡) -methanone;
(172) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-p¡razol-4-il]-(5-benc¡lox¡-1H-¡ndol-2-¡l)-metanona;(172) [5-amine-1- (2-methyl-1H-benzimidazol-5-yl) -1H-p¡razol-4-yl] - (5-benzyllox¡-1H-¡ ndol-2-¡l) -methanone;
(173) [5-amino-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-il]-(4-benc¡lox¡-1H-¡ndol-2-¡l)-metanona;(173) [5-amino-1- (2-methyl-1H-benzimdazol-5-l) -1H-p¡razol-4-yl] - (4-benzyllox¡-1H- Ndol-2-¡l) -methanone;
(174) [5-am¡no-1-(2-met¡l-1H-bencim¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(5,6-d¡metox¡-1H-¡ndol-2-¡l)-metanona;(174) [5-am-1-1 (2-methyl-1H-benzimdazol-5-l) -1H-p.razole-4-l] - (5,6-d¡ metox¡-1H-¡ndol-2-¡l) -methanone;
(175) [5-am¡no-1-(2-met¡l-1H-benc¡midazol-5-¡l)-1H-p¡razol-4-¡l]-(6-ferí-but¡l-1H-¡ndol-2-¡l)-metanona;(175) [5-am-1-1 (2-methyl-1H-benzylmidazol-5-l) -1 H-p.razole-4-l] - (6-feri-but) l-1H-¡ndol-2-¡l) -methanone;
(176) [5-am¡no-1-(2-met¡l-1H-benc¡midazol-5-¡l)-1H-p¡razol-4-¡l]-(5-fluoro-4-tr¡fluoromet¡l-1H-¡ndol-2-¡l)-metanona;(176) [5-am-no-1- (2-methyl-1H-benzylmidazol-5-l) -1H-p¡razol-4-l] - (5-fluoro-4- trfluorometl-1H-¡ndol-2-¡l) -methanone;
(177) [5-am¡no-1-(2-met¡l-1H-bencim¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(5-fenox¡-1H-¡ndol-2-¡l)-metanona;(177) [5-am-1-1 (2-methyl-1H-benzimdazol-5-l) -1H-p.razole-4-l] - (5-phenoxy-1H -¡Ndol-2-¡l) -methanone;
(178) [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-p¡razol-4-il]-(6-metilsulfan¡l-1 H-indol-2-il )-metanona;(178) [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hp¡razol-4-yl] - (6-methylsulfan¡l-1 H-indole-2-yl ) -methanone;
(179) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-¡l)-1H-pirazol-4-¡l]-(4-fert-but¡l-1H-¡ndol-2-il)-metanona;(179) [5-am-1-1 (2-methyl-1H-benzimidazol-5-l) -1 H -pyrazol-4-l] - (4-fert-but-l-1H- Ndol-2-yl) -methanone;
(180) [5-amino-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-il]-(5-met¡l-1H-indol-2-¡l)-metanona;(180) [5-Amino-1- (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-yl] - (5-methyl-1H-indole-2 -L) -methanone;
(181) [5-amino-1-(2-metil-1 H-benc¡m¡dazol-5-¡l)-1 H-pirazol-4-il]-(5-etil-1 H-indol-2-il)-metanona;(181) [5-amino-1- (2-methyl-1 H-benzimdazol-5-yl) -1 H -pyrazol-4-yl] - (5-ethyl-1 H-indole- 2-yl) -methanone;
(182) [5-amino-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-il]-(5-fluoro-6-trifluoromet¡l-1H-¡ndol-2-il)-metanona;(182) [5-amino-1- (2-methyl-1H-benzimdazol-5-yl) -1 H -pyrazol-4-yl] - (5-fluoro-6-trifluoromet-1-H -¡Ndol-2-yl) -methanone;
(183) [5-amino-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-il]-(6-fluoro-5-metoxi-1H-¡ndol-2 -il)-metanona;(183) [5-amino-1- (2-methyl-1H-benzimdazol-5-l) -1H-pyrazol-4-yl] - (6-fluoro-5-methoxy-1H-¡ ndol-2-yl) -methanone;
(184) [5-amino-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-il]-(6-cloro-5-metoxi-1H-¡ndol-2-il)-metanona;(184) [5-amino-1- (2-methyl-1H-benzimdazol-5-yl) -1H-pyrazol-4-yl] - (6-chloro-5-methoxy-1H-¡ ndol-2-yl) -methanone;
(185) [5-amino-1-(2-metil-1H-bencim¡dazol-5-¡l)-1H-p¡razol-4-il]-(5-cloro-6-metox¡-1H-¡ndol-2-il)-metanona;(185) [5-amino-1- (2-methyl-1H-benzimdazol-5-yl) -1 H -pyrazol-4-yl] - (5-chloro-6-methoxy-1H- Ndol-2-yl) -methanone;
(186) [5-amino-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-il]-(6-¡sopropox¡-1H-¡ndol-2-¡l)-metanona;(186) [5-amino-1- (2-methyl-1H-benzimdazol-5-l) -1H-p¡razol-4-yl] - (6-sopropox¡-1H-¡ ndol-2-¡l) -methanone;
(187) [5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(6-benc¡lox¡-1H-¡ndol-2-¡l)-metanona;(187) [5-amino-1- (2-methyl-1H-benzyldazol-5-ll) -1 H -pyrazol-4-l] - (6-benzyllox) -1H-¡ndol-2-¡l) -methanone;
(188) [5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(4-¡sopropox¡-1H-¡ndol-2-¡l)-metanona;(188) [5-amino-1- (2-methyl-1H-benzyldazol-5-l) -1H-p¡razol-4-l] - (4-sopropox) 1H-¡ndol-2-¡l) -methanone;
(189) [5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(2,3-d¡h¡dro-6H-[1,4]d¡ox¡no[2, 3-f]indol-7-il)- metanona;(189) [5-amino-1- (2-methyl-1H-benzyldazol-5-α) -1H-pyrolol-4-α] - (2,3-d¡ water-6H- [1,4] doxox [2,3-f] indole-7-yl) -methanone;
(190) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-p¡razol-4-il]-(4,6-di-íerf-butil-1 H-indol-2-il) -metanona;(190) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 Hp¡razol-4-yl] - (4,6-di-íerf-butyl-1 H-indole -2-yl) -methanone;
(191) 2-[5-amino-1 -(2-met¡l-1 H-bencim¡dazol-5-¡l)-1 H-pirazol-4-carbonil]-1 H-indol-4-carbonitrilo;(191) 2- [5-amino-1 - (2-methyl-1 H-benzimdazol-5-l) -1 H -pyrazol-4-carbonyl] -1 H-indole-4-carbonitrile ;
(192) [5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-il]-(5-¡m¡dazol-1-il-1H-¡ndol-2-il) -metanona;(192) [5-amino-1- (2-methyl-1H-benzyldazol-5-yl) -1 H-prazol-4-yl] - (5-mdadazol- 1-il-1H-¡ndol-2-yl) -methanone;
(193) [5-amino-1-(2-metil-1H-bencimidazol-5-¡l)-1H-p¡razol-4-il]-(5-trifluoromet¡lsulfan¡l-1H-indol-2-¡l)-metanona;(193) [5-amino-1- (2-methyl-1H-benzimidazol-5-1) -1H-p¡razol-4-yl] - (5-trifluorometlslsulfan¡l-1H-indole-2 -L) -methanone;
(194) [5-amino-1-(2-metil-1H-bencimidazol-5-¡l)-1H-p¡razol-4-il]-(5-metilsulfan¡l-1H-¡ndol-2-il )-metanona;(194) [5-Amino-1- (2-methyl-1H-benzimidazol-5-1) -1H-p¡razol-4-yl] - (5-methylsulfan¡l-1H-¡ndol-2- il) -methanone;
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(195) [5-am¡no-1-(2-met¡l-1H-bencim¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(5-metanosulfon¡l-1H-¡ndol-2-¡l)-metanona;(195) [5-am-1-1 (2-methyl-1H-benzimdazol-5-l) -1 H-p.razol-4-l] - (5-methanesulfonl) 1H-¡ndol-2-¡l) -methanone;
(196) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pi razol-4-il]-[6-(4,4-difluoro-piperidi n-1 -ilmetil)-1 H-indol- 2-il]-(196) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pi razol-4-yl] - [6- (4,4-difluoro-piperidi n-1 -ylmethyl) -1 H-indole-2-yl] -
metanona;methanone;
(197) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-(4-fluoro-p¡ peridin-1 -ilmetil)-1 H-indol-2-il]- metanona;(197) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6- (4-fluoro-p¡ peridin-1-methylmethyl) ) -1 H-indol-2-yl] - methanone;
(198) [5-am¡no-1-(2-met¡l-1H-bencim¡dazol-5-¡l)-1H-p¡razol-4-¡l]-[6-(oxetan-3-¡lox¡)-1H-¡ndol-2-¡l]-metanona;(198) [5-am-1-1 (2-methyl-1H-benzimdazol-5-l) -1H-p.razole-4-l] - [6- (oxetan-3 -¡Lox¡) -1H-¡ndol-2-¡l] -methanone;
(199) [5-am¡no-1-(2-met¡l-1H-bencim¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(6-h¡drox¡-1H-¡ndol-2-¡l)-metanona;(199) [5-am-1-1 (2-methyl-1H-benzimdazol-5-l) -1H-p.razole-4-l] - (6-h. -1H-¡ndol-2-¡l) -methanone;
(200) [5-am¡no-1-(2-met¡l-1H-bencim¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(6-metanosulfon¡l-1H-¡ndol-2-¡l)-metanona;(200) [5-am-1-1 (2-methyl-1H-benzimdazol-5-l) -1 H-p.razol-4-l] - (6-methanesulfonl) 1H-¡ndol-2-¡l) -methanone;
(201) [5-am¡no-1-(2-met¡l-1H-bencim¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(4,5-d¡bromo-1H-p¡rrol-2-¡l)-metanona;(201) [5-am-1-1 (2-methyl-1H-benzimdazol-5-l) -1H-p.razole-4-l] - (4,5-d¡ Bromo-1H-pyrrol-2-l) -methanone;
(202) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-(4,5-difenil-1 H-pirrol-2-il)-metanona; y(202) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (4,5-diphenyl-1 H -pyrrol-2-yl ) -methanone; Y
(203) [5-am¡no-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-(4,5-dipiridin-3-il-1 H-pirrol-2-il)-metanona.(203) [5-amine-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (4,5-dipyridin-3-yl-1 H -pyrrol-2-yl) -methanone.
[106] Una composición farmacéutica que comprende el compuesto de uno cualquiera de [101] a [105], o una sal farmacéuticamente aceptable del mismo; y un portador.[106] A pharmaceutical composition comprising the compound of any one of [101] to [105], or a pharmaceutically acceptable salt thereof; and a carrier.
[107] (no reivindicado) Un agente para la inhibición de la actividad del FGFR, que comprende como un ingrediente activo el compuesto de uno cualquiera de [101] a [105], o una sal farmacéuticamente aceptable del mismo.[107] (not claimed) An agent for the inhibition of FGFR activity, which comprises as an active ingredient the compound of any one of [101] to [105], or a pharmaceutically acceptable salt thereof.
[108] Un agente para prevenir o tratar el cáncer, que comprende como un ingrediente activo el compuesto de uno cualquiera de [101] a [105], o una sal farmacéuticamente aceptable del mismo.[108] An agent for preventing or treating cancer, which comprises as an active ingredient the compound of any one of [101] to [105], or a pharmaceutically acceptable salt thereof.
[109] El agente para uso en un método de prevención o tratamiento del cáncer de [108], en donde el cáncer es al menos uno seleccionado del grupo que consiste en: cáncer de mama, leucemia mielocítica aguda, cáncer de páncreas, cáncer de vejiga, cáncer de próstata, cáncer de esófago, angiogénesis, cáncer de estómago, cáncer de cuerpo uterino, cáncer de ovario, tumor cerebral, cáncer de colon, mieloma múltiple, hepatocarcinoma, cáncer pulmonar, y cáncer de tiroides.[109] The agent for use in a cancer prevention or treatment method of [108], wherein the cancer is at least one selected from the group consisting of: breast cancer, acute myelocytic leukemia, pancreatic cancer, cancer of Bladder, prostate cancer, esophageal cancer, angiogenesis, stomach cancer, uterine body cancer, ovarian cancer, brain tumor, colon cancer, multiple myeloma, hepatocarcinoma, lung cancer, and thyroid cancer.
[110] Una composición que comprende el compuesto de uno cualquiera de [101] a [105] o una sal farmacéuticamente aceptable del mismo para uso en un método para prevenir o tratar el cáncer, que comprende administrar una cantidad farmacéuticamente efectiva de dicha composición a un paciente en necesidad de prevención o tratamiento del cáncer.[110] A composition comprising the compound of any one of [101] to [105] or a pharmaceutically acceptable salt thereof for use in a method of preventing or treating cancer, which comprises administering a pharmaceutically effective amount of said composition to a patient in need of prevention or treatment of cancer.
[111] Uso del compuesto de uno cualquiera de [101] a [105] o una sal farmacéuticamente aceptable del mismo en la producción de un agente para prevenir o tratar el cáncer.[111] Use of the compound of any one of [101] to [105] or a pharmaceutically acceptable salt thereof in the production of an agent to prevent or treat cancer.
[112] El compuesto de uno cualquiera de [101] a [105] o una sal farmacéuticamente aceptable del mismo, para uso en un método de prevención o tratamiento del cáncer.[112] The compound of any one of [101] to [105] or a pharmaceutically acceptable salt thereof, for use in a method of cancer prevention or treatment.
[Efectos de la invención][Effects of the invention]
Los compuestos de la presente invención y descripción y las sales farmacéuticamente aceptables del mismo tienen la actividad de inhibición de las quinasas de la familia del FGFR en tejidos de cáncer. Adicionalmente, los compuestos de la presente invención y descripción pueden ejercer eficacia sobre nuevos genes (genes no dirigidos) alterados en el cáncer, y por lo tanto puede prevenir y/o tratar cánceres contra los cuales ninguna terapia eficaz está disponible.The compounds of the present invention and description and pharmaceutically acceptable salts thereof have the activity of inhibition of the kinases of the FGFR family in cancer tissues. Additionally, the compounds of the present invention and description can exert efficacy on new genes (non-targeted genes) altered in cancer, and therefore can prevent and / or treat cancers against which no effective therapy is available.
Modo de llevar a cabo la invenciónWay of carrying out the invention
La presente invención y descripción se relacionan con derivados de aminopirazol y usos de los mismos. Los presentes inventores sintetizaron por primera vez los compuestos representados por formula (I) mostrada anteriormente o las sales farmacéuticamente aceptables de los mismos y descubrieron que los compuestos o las sales de los mismos tienen la actividad de inhibición de las quinasas de la familia del FGFR.The present invention and description relate to aminopyrazole derivatives and uses thereof. The present inventors first synthesized the compounds represented by formula (I) shown above or the pharmaceutically acceptable salts thereof and found that the compounds or salts thereof have the activity of inhibition of the kinases of the FGFR family.
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En este documento, el "alquilo" se refiere a un grupo monovalente derivado a partir de un hidrocarburo alifático por eliminación de un átomo de hidrógeno arbitrario. No contiene heteroátomo ni enlace carbono-carbono insaturado en el esqueleto, y tiene un subconjunto de las estructuras del grupo hidrocarbilo o hidrocarburo que contienen hidrógeno y átomos de carbono. El grupo alquilo incluye estructuras lineales y ramificadas. Los grupos alquilo preferidos incluyen grupos alquilo con uno a seis átomos de carbono (C1.6; de ahora en adelante, "Cp.q" significa que el número de átomos de carbono es p a q), grupos alquilo C1.5, grupos alquilo C1.4, y grupos alquilo C1.3.In this document, "alkyl" refers to a monovalent group derived from an aliphatic hydrocarbon by removal of an arbitrary hydrogen atom. It contains no heteroatom or unsaturated carbon-carbon bond in the skeleton, and has a subset of the hydrocarbyl or hydrocarbon group structures containing hydrogen and carbon atoms. The alkyl group includes linear and branched structures. Preferred alkyl groups include alkyl groups with one to six carbon atoms (C1.6; hereafter, "Cp.q" means that the number of carbon atoms is paq), C1.5 alkyl groups, C1 alkyl groups .4, and C1.3 alkyl groups.
Específicamente, el alquilo incluye, por ejemplo, grupo metilo, grupo etilo, grupo n-propilo, grupo isopropilo, grupo n- butilo, grupo isobutilo, grupo s-butilo, grupo t-butilo, grupo pentilo, grupo isopentilo, grupo 2,3-dimetilpropilo, grupo 3,3-dimetilbutilo, y grupo hexilo.Specifically, the alkyl includes, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, t-butyl group, pentyl group, isopentyl group, group 2, 3-dimethylpropyl, 3,3-dimethylbutyl group, and hexyl group.
En este documento, "alquenilo" se refiere a un grupo hidrocarburo monovalente que tiene al menos un doble enlace (dos átomos de carbono SP2 adyacentes), e incluye aquellos de formas lineal y ramificada. Dependiendo de la configuración del doble enlace y los sustituyentes (si existen), la geometría del doble enlace puede ser de configuración entgegen (E) o zusammen (Z), o cis o trans. Los grupos alquenilo preferido incluyen grupos alqueniloIn this document, "alkenyl" refers to a monovalent hydrocarbon group having at least one double bond (two adjacent SP2 carbon atoms), and includes those of linear and branched forms. Depending on the configuration of the double bond and the substituents (if any), the geometry of the double bond may be entgegen (E) or zusammen (Z), or cis or trans. Preferred alkenyl groups include alkenyl groups.
C2-6-C2-6-
Específicamente, el alquenilo incluye, por ejemplo, grupo vinilo, grupo alilo, grupo 1-propenilo, grupo 2-propenilo, grupo 1- butenilo, grupo 2-butenilo (incluyendo cis y trans), grupo 3-butenilo, grupo pentenilo, y grupo hexenilo.Specifically, the alkenyl includes, for example, vinyl group, allyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group (including cis and trans), 3-butenyl group, pentenyl group, and hexenyl group.
En este documento, "alquinilo" se refiere a un grupo hidrocarburo monovalente que tiene al menos un enlace triple (dos átomos de carbono SP adyacentes), e incluye aquellos de formas lineal y ramificada. Los grupos alquinilo preferidos incluyen grupos alquinilo C2-6.In this document, "alkynyl" refers to a monovalent hydrocarbon group having at least one triple bond (two adjacent SP carbon atoms), and includes those in a linear and branched form. Preferred alkynyl groups include C2-6 alkynyl groups.
Específicamente, el alquinilo incluye, por ejemplo, grupo tinilo, grupo 1-propinilo, grupo propargilo, grupo 3-butinilo,Specifically, the alkynyl includes, for example, tinyl group, 1-propynyl group, propargyl group, 3-butynyl group,
grupo pentinilo, y grupo hexinilo.pentinyl group, and hexinyl group.
El alquenilo y alquinilo puede cada uno tener uno o más dobles enlaces o triples enlaces.The alkenyl and alkynyl can each have one or more double bonds or triple bonds.
En este documento, "cicloalquilo" se refiere a un grupo hidrocarburo alifático monovalente cíclico saturado o parcialmente saturado, e incluye grupos monocíclicos, anillos bicíclicos, y anillos espiro. El cicloalquilo preferido incluye grupos cicloalquilo C3-7. Específicamente, el grupo cicloalquilo incluye, por ejemplo, grupo ciclopropilo, grupo ciclobutilo, grupo ciclopentilo, grupo ciclohexiol, y grupo cicloheptilo.In this document, "cycloalkyl" refers to a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group, and includes monocyclic groups, bicyclic rings, and spiro rings. The preferred cycloalkyl includes C3-7 cycloalkyl groups. Specifically, the cycloalkyl group includes, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyol group, and cycloheptyl group.
En este documento, "cicloalquilalquilo" se refiere a un grupo en el cual un átomo de hidrógeno arbitrario de un "alquilo" definido anteriormente es sustituido con un "cicloalquilo" definido anteriormente. Los grupos cicloalquilalquilo preferidos incluyen cicloalquilo C3-7-alquilo C1-3, y específicamente incluye, por ejemplo, grupo ciclopropil metilo y grupo ciclopropil etilo.In this document, "cycloalkylalkyl" refers to a group in which an arbitrary hydrogen atom of a "alkyl" defined above is substituted with a "cycloalkyl" defined above. Preferred cycloalkylalkyl groups include C3-7 cycloalkyl-C1-3alkyl, and specifically includes, for example, cyclopropyl methyl group and cyclopropyl ethyl group.
En este documento, "heteroátomo" se refiere a un átomo de nitrógeno (N), átomo de oxígeno (O), o átomo de azufreIn this document, "heteroatom" refers to a nitrogen atom (N), oxygen atom (O), or sulfur atom
(S).(S)
En este documento, "átomo de halógeno" se refiere a un átomo de flúor, átomo de cloro, átomo de bromo, o átomo de yodo.In this document, "halogen atom" refers to a fluorine atom, chlorine atom, bromine atom, or iodine atom.
En este documento, "haloalquilo" se refiere a un grupo en el cual preferiblemente de uno a nueve, más preferiblemente uno a cinco "átomos de halógeno" idénticos o diferentes definidos anteriormente se unen a un "alquilo" definido anteriormente.In this document, "haloalkyl" refers to a group in which preferably one to nine, more preferably one to five identical or different "halogen atoms" defined above are linked to a "alkyl" defined above.
Específicamente, el haloalquilo incluye, por ejemplo, grupo clorometilo, grupo diclorometilo, grupo triclorometilo, grupo fluorometilo, grupo difluorometilo, grupo perfluoroalquilo (tales como grupo trifluorometilo y -CF2CF3), y grupo 2,2,2-trifluoro etilo.Specifically, the haloalkyl includes, for example, chloromethyl group, dichloromethyl group, trichloromethyl group, fluoromethyl group, difluoromethyl group, perfluoroalkyl group (such as trifluoromethyl group and -CF2CF3), and 2,2,2-trifluoro ethyl group.
En este documento, "alcoxi" se refiere a un grupo oxi unido con un "alquilo" definido anteriormente. Alcoxi preferido incluye grupos alcoxi C1.4 y grupos alcoxi Ci_3. Específicamente, alcoxi incluye, por ejemplo, grupo metoxi, grupo etoxi, grupo 1- propoxi, grupo 2-propoxi, grupo n-butoxi, grupo i-butoxi, grupo sec-butoxi, y grupo fert-butoxi.In this document, "alkoxy" refers to an oxy group linked with an "alkyl" defined above. Preferred alkoxy includes C1.4 alkoxy groups and C__3 alkoxy groups. Specifically, alkoxy includes, for example, methoxy group, ethoxy group, 1- propoxy group, 2-propoxy group, n-butoxy group, i-butoxy group, sec-butoxy group, and fert-butoxy group.
En este documento, "haloalcoxi" se refiere a un grupo en el cual preferiblemente de uno a nueve, más preferiblemente de uno a cinco átomos de halógeno idénticos o diferentes definidos anteriormente se unen a un "alcoxi" definido anteriormente.In this document, "haloalkoxy" refers to a group in which preferably one to nine, more preferably one to five identical or different halogen atoms defined above are attached to a "alkoxy" defined above.
Específicamente, el haloalcoxi incluye, por ejemplo, grupo clorometoxi, grupo triclorometoxi, y grupo trifluorometoxi.Specifically, the haloalkoxy includes, for example, chloromethoxy group, trichloromethoxy group, and trifluoromethoxy group.
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En este documento, "arilo" se refiere a un anillo de hidrocarburo aromático monovalente. El arilo preferiblemente incluye arilo C6-10. Específicamente, el arilo incluye, por ejemplo, grupo fenilo y grupos naftilo (por ejemplo, grupo 1- naftilo y grupo 2-naftilo).In this document, "aryl" refers to a monovalent aromatic hydrocarbon ring. The aryl preferably includes C6-10 aryl. Specifically, the aryl includes, for example, phenyl group and naphthyl groups (for example, 1-naphthyl group and 2-naphthyl group).
En este documento, "anillo alicíclico" se refiere a un anillo de hidrocarburo no-aromático monovalente. El anillo alicíclico puede tener enlaces insaturados dentro de su anillo, y puede ser un grupo multicíclico que tiene dos o más anillos. Los átomos de carbono que constituyen el anillo se pueden oxidar para formar un carbonilo. El número de átomos que constituye un anillo alicíclico preferiblemente oscila entre tres a diez (de 3- a 10- miembros anillo alifático). El anillo alicíclico incluye, por ejemplo, anillos cicloalquilo, anillos cicloalquenilo, y anillos cicloalquinilo.In this document, "alicyclic ring" refers to a monovalent non-aromatic hydrocarbon ring. The alicyclic ring may have unsaturated bonds within its ring, and it may be a multicyclic group having two or more rings. The carbon atoms that make up the ring can be oxidized to form a carbonyl. The number of atoms that constitute an alicyclic ring preferably ranges from three to ten (3- to 10-aliphatic ring members). The alicyclic ring includes, for example, cycloalkyl rings, cycloalkenyl rings, and cycloalkynyl rings.
En este documento, "heteroarilo" se refiere a un grupo heterocíclico aromático monovalente en el cual los átomos que constituyen el anillo incluyen preferiblemente de uno a cinco heteroátomos. El heteroarilo puede ser parcialmente saturado, y puede ser un anillo monocíclico o condensado (por ejemplo, un heteroarilo bicíclico condensado con un anillo de benceno o anillo de heteroarilo monocíclico). El número de átomos que constituyen el anillo preferiblemente oscila entre cinco a diez (heteroarilo de 5- a 10- miembros).In this document, "heteroaryl" refers to a monovalent aromatic heterocyclic group in which the atoms that constitute the ring preferably include one to five heteroatoms. The heteroaryl may be partially saturated, and may be a monocyclic or fused ring (for example, a bicyclic heteroaryl fused to a benzene ring or monocyclic heteroaryl ring). The number of atoms that constitute the ring preferably ranges from five to ten (5- to 10-membered heteroaryl).
Específicamente, el heteroarilo incluye, por ejemplo, grupo furilo, grupo tienilo, grupo pirrolilo, grupo imidazolilo, grupo pirazolilo, grupo tiazolilo, grupo isotiazolilo, grupo oxazolilo, grupo isooxazolilo, grupo oxadiazolilo, grupo tiadiazolilo, grupo triazolilo, grupo tetrazolilo, grupo piridilo, grupo pirimidilo, grupo piridazinilo, grupo pirazinilo, grupo triazinilo, grupo benzofuranilo, grupo benzotienilo, benzotiadiazolilo grupo, grupo benzotiazolilo, grupo benzoxazolilo, grupo benzoxadiazolilo, grupo benzoimidazolilo, grupo indolilo, grupo isoindolilo, grupo azaindolilo, grupo indazolilo, grupo quinolilo, grupo isoquinolilo, grupo cinolinilo, grupo quinazolinilo, grupo quinoxalinilo, grupo benzodioxolilo, grupo indolidinilo, y el grupo imidazopiridilo.Specifically, the heteroaryl includes, for example, furyl group, thienyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isooxazolyl group, oxadiazolyl group, thiadiazolyl group, triazolyl group, tetrazolyl group, pyridyl group , pyrimidyl group, pyridazinyl group, pyrazinyl group, triazinyl group, benzofuranyl group, benzothienyl group, benzothiadiazolyl group, benzothiazolyl group, benzoxazolyl group, benzoxadiazolyl group, benzoimidazolyl group, indolyl group, isoindolyl group, azazole group isoquinolyl, cinolinyl group, quinazolinyl group, quinoxalinyl group, benzodioxolyl group, indolidinyl group, and the imidazopyridyl group.
En este documento, "heterociclilo" se refiere a un grupo heterocíclico no-aromático monovalente en el cual los átomos que constituyen el anillo incluyen preferiblemente uno a cinco heteroátomos. El heterociclilo puede contener enlaces dobles o triples en su anillo. Los átomos de carbono pueden ser oxidados para formar un carbonilo. El anillo puede ser un anillo monocíclico o condensado. El número de los átomos que constituyen el anillo preferiblemente oscila entre tres a diez (heterociclilo de 3- a 10- miembros).In this document, "heterocyclyl" refers to a monovalent non-aromatic heterocyclic group in which the atoms that constitute the ring preferably include one to five heteroatoms. The heterocyclyl may contain double or triple bonds in its ring. Carbon atoms can be oxidized to form a carbonyl. The ring may be a monocyclic or condensed ring. The number of atoms that constitute the ring preferably ranges from three to ten (3- to 10-membered heterocyclyl).
Específicamente, el heterociclilo incluye, por ejemplo, grupo oxetanilo, grupo dihidrofurilo, grupo tetrahidrofurilo, grupo dihidropiranilo, grupo tetrahidropiranilo, grupo tetrahidropiridilo, grupo morfolinilo, tiomorfolinilo, grupo pirrolidinilo, grupo piperidinilo, grupo piperazinilo, grupo pirazolidinilo, grupo imidazolinilo , grupo imidazolidinilo, grupo oxazolidinilo, grupo isooxazolidinilo, grupo tiazolidinilo, grupo isotiazolidinilo, grupo tiadiazolidinilo, grupo azetidinilo, grupo oxazolidona, grupo benzodioxanilo, grupo benzoxazolilo, grupo dioxolanilo, y el grupo dioxanilo.Specifically, the heterocyclyl includes, for example, oxetanyl group, dihydrofuryl group, tetrahydrofuryl group, dihydropyranyl group, tetrahydropyranyl group, tetrahydropyridyl group, morpholinyl group, thiomorpholinyl, pyrrolidinyl group, piperidinyl group, piperazinyl group, imidazidazolidyl group, imidazidazolidyl group oxazolidinyl group, isooxazolidinyl group, thiazolidinyl group, isothiazolidinyl group, thiadiazolidinyl group, azetidinyl group, oxazolidone group, benzodioxanyl group, benzoxazolyl group, dioxolanyl group, and dioxanyl group.
En este documento, "arilalquilo" se refiere a un grupo en el cual un átomo de hidrógeno arbitrario en un "alquilo" definido anteriormente es sustituido con un "arilo" definido anteriormente. El arilalquilo preferiblemente incluye arilo Ce-io alquilo C-m y arilo C6-io alquilo Ci_3. Específicamente, el arilalquilo incluye, por ejemplo, grupo bencilo, grupo fenetilo, y grupo naftilmetilo.In this document, "arylalkyl" refers to a group in which an arbitrary hydrogen atom in a "alkyl" defined above is substituted with an "aryl" defined above. The arylalkyl preferably includes aryl Ce-io C-m alkyl and aryl C6-io Ci_3 alkyl. Specifically, the arylalkyl includes, for example, benzyl group, phenethyl group, and naphthylmethyl group.
En este documento, "heteroarilalquilo" se refiere a un grupo en el cual un átomo de hidrógeno arbitrario en un alquilo definido anteriormente es sustituido con un "heteroarilo" definido anteriormente. El heteroarilalquilo preferiblemente incluye heteroarilo de 5- a 10- miembros alquilo C1.3. Específicamente, el heteroarilalquilo incluye, por ejemplo, grupo pirrolilmetilo, grupo ¡midazolilmetilo, grupo tienilmetilo, grupo piridilmetilo, grupo pirimidilmetilo, grupo quinolilmetilo, y grupo piridiletilo.In this document, "heteroarylalkyl" refers to a group in which an arbitrary hydrogen atom in a previously defined alkyl is substituted with a "heteroaryl" defined above. The heteroarylalkyl preferably includes 5- to 10-membered C1.3 alkyl heteroaryl. Specifically, the heteroarylalkyl includes, for example, pyrrolylmethyl group, midazolylmethyl group, thienylmethyl group, pyridylmethyl group, pyrimidylmethyl group, quinolylmethyl group, and pyridylethyl group.
En este documento, "heterociclilalquilo" se refiere a un grupo en el cual un átomo de hidrógeno arbitrario en un “alquilo” definido anteriormente es sustituido con un "heterociclilo" definido anteriormente. El heterociclilalquilo preferiblemente incluye heterociclilo de 3- a 10- miembros alquilo C1-3. Específicamente, el heterociclilalquilo incluye, por ejemplo, grupo morfolinilmetilo, grupo morfoliniletilo, grupo tiomorfolinilmetilo, grupo pirrolidinilmetilo, grupo piperidinilmetilo, grupo piperazinilmetilo, grupo piperaziniletilo, y grupo oxetanilmetilo.In this document, "heterocyclylalkyl" refers to a group in which an arbitrary hydrogen atom in a "alkyl" defined above is substituted with a "heterocyclyl" defined above. The heterocyclyl alkyl preferably includes 3- to 10-membered C1-3 alkyl heterocyclyl. Specifically, the heterocyclylalkyl includes, for example, morpholinylmethyl group, morpholinyl methyl group, thiomorpholinylmethyl group, pyrrolidinylmethyl group, piperidinylmethyl group, piperazinylmethyl group, piperazinylethyl group, and oxetanylmethyl group.
En este documento, "monohidroxialquilo" se refiere a un grupo en el cual un átomo de hidrógeno arbitrario en un “alquilo” definido anteriormente es sustituido con un grupo hidroxilo. El monohidroxialquilo preferiblemente incluye monohidroxialquilo Ci_6 y monohidroxialquilo C2-6. Específicamente, el monohidroxialquilo incluye, por ejemplo, grupo hidroximetilo, 1-grupo ehidroxitilo, y grupo 2-hidroxi etilo.In this document, "monohydroxyalkyl" refers to a group in which an arbitrary hydrogen atom in a "alkyl" defined above is substituted with a hydroxyl group. The monohydroxyalkyl preferably includes Ci_6 monohydroxyalkyl and C2-6 monohydroxyalkyl. Specifically, the monohydroxyalkyl includes, for example, hydroxymethyl group, 1-ethylhydroxy group, and 2-hydroxy ethyl group.
En este documento, “dihidroxialquilo” se refiere a un grupo en el cual dos átomos de hidrógeno arbitrarios en un “alquilo” definido anteriormente son sustituidos con dos grupos hidroxilos. El dihidroxialquilo preferiblemente incluye dihidroxialquilo Ci_6 y C2-6 dihidroxialquilo. Específicamente, el dihidroxialquilo incluye, por ejemplo, grupo 1,2- dihidroxietilo, grupo 1,2-dihidroxipropilo, y grupo 1,3-dihidroxipropilo.In this document, "dihydroxyalkyl" refers to a group in which two arbitrary hydrogen atoms in an "alkyl" defined above are substituted with two hydroxyl groups. The dihydroxyalkyl preferably includes Ci_6 dihydroxyalkyl and C2-6 dihydroxyalkyl. Specifically, the dihydroxyalkyl includes, for example, 1,2-dihydroxyethyl group, 1,2-dihydroxypropyl group, and 1,3-dihydroxypropyl group.
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En este documento, "trihidroxialquilo" se refiere a un grupo en el cual tres átomos de hidrógeno arbitrarios en un “alquilo” definido anteriormente son sustituidos con tres grupos hidroxilos. El trihidroxialquilo preferiblemente incluye trihidroxialquilo Ci.6 y trihidroxialquilo C2-6.In this document, "trihydroxyalkyl" refers to a group in which three arbitrary hydrogen atoms in an "alkyl" defined above are substituted with three hydroxyl groups. The trihydroxyalkyl preferably includes trihydroxyalkyl Ci.6 and trihydroxyalkyl C2-6.
En este documento, "alcoxialquilo" se refiere a un grupo en el cual un átomo de hidrógeno arbitrario en un “alquilo” definido anteriormente es sustituido con un "alcoxi" definido anteriormente. El alcoxialquilo preferiblemente incluye alcoxl C-i-3 alquilo Ci_4y alcoxi Ci_3 alquilo C2.4. Específicamente, el alcoxialquilo incluye, por ejemplo, metoxietilo.In this document, "alkoxyalkyl" refers to a group in which an arbitrary hydrogen atom in a "alkyl" defined above is substituted with a "alkoxy" defined above. The alkoxyalkyl preferably includes C-i-3 alkoxy Ci_4 alkyl and Ci_3 alkoxy C2.4 alkyl. Specifically, the alkoxyalkyl includes, for example, methoxyethyl.
En este documento, "alcoxialcoxialquilo" se refiere a un grupo en el cual un átomo de hidrógeno arbitrario en el terminal alquilo de un "alcoxialquilo" definido anteriormente es sustituido con un "alcoxi" definido anteriormente. El alcoxialcoxialquilo preferiblemente incluye alcoxi C1.3 alcoxi C1.4 alquilo C1.4 y alcoxi C1.3 alcoxi C2-4 alquilo C2-4.In this document, "alkoxyalkoxyalkyl" refers to a group in which an arbitrary hydrogen atom in the alkyl terminal of a "alkoxyalkyl" defined above is substituted with a "alkoxy" defined above. The alkoxyalkoxyalkyl preferably includes C1.3 alkoxy C1.4 alkoxy C1.4 alkyl and C1.3 alkoxyC2-4 alkoxyC2-4 alkyl.
En este documento, "aminoalquilo" se refiere a un grupo en el cual un átomo de hidrógeno arbitrario en un “alquilo” definido anteriormente es sustituido con un grupo amino. El grupo aminoalquilo preferiblemente incluye aminoalquilo C1.4 y aminoalquilo C2-4.In this document, "aminoalkyl" refers to a group in which an arbitrary hydrogen atom in an "alkyl" defined above is substituted with an amino group. The aminoalkyl group preferably includes C1.4 aminoalkyl and C2-4 aminoalkyl.
En este documento, "alquilamino" se refiere a un grupo amino unido con un “alquilo” definido anteriormente. El alqullamino preferiblemente incluye alquilamino C1.4.In this document, "alkylamino" refers to an amino group linked with an "alkyl" defined above. The alqullamino preferably includes C1.4 alkylamino.
En este documento, "dialquilamino" se refiere a un grupo amino unido con dos "alquilos" definidos anteriormente. Los dos grupos alquilo pueden ser iguales o diferentes. El dialquilamino preferiblemente incluye di(alquilo C-i_ 4)amino.In this document, "dialkylamino" refers to an amino group linked with two "alkyls" defined above. The two alkyl groups may be the same or different. The dialkylamino preferably includes di (C-i_ 4 alkyl) amino.
En este documento, "alquilaminoalquilo" se refiere a un grupo en el cual un átomo de hidrógeno arbitrario en un “alquilo” definido anteriormente es sustituido con un "alquilamino" definido anteriormente. El alquilaminoalquilo preferiblemente incluye alquilamino C1.4 alquilo Ci_4y alquilamino C1.4 alquilo C2-4.In this document, "alkylaminoalkyl" refers to a group in which an arbitrary hydrogen atom in an "alkyl" defined above is substituted with an "alkylamino" defined above. The alkylaminoalkyl preferably includes C1.4 alkylaminoCi_4 alkyl and C1.4 alkylaminoC2-4 alkyl.
En este documento, "dialquilaminoalquilo" se refiere a un grupo en el cual un átomo de hidrógeno arbitrario en un “alquilo” definido anteriormente es sustituido con un "dialquilamino" definido anteriormente. El dialquilaminoalquilo preferiblemente Incluye di(alquilo Ci.4)amino alquilo Ci_4y di(alquilo C-Mjamino alquilo C2-4.In this document, "dialkylaminoalkyl" refers to a group in which an arbitrary hydrogen atom in a "alkyl" defined above is substituted with a "dialkylamino" defined above. The dialkylaminoalkyl preferably includes di (Ci 4 alkyl) amino Ci_4 alkyl and di (C-Mjamino alkyl C2-4 alkyl.
En este documento, "heterociclilamino" se refiere a un grupo amino unido con un "heterociclilo" definido anteriormente. El heterociclilamino preferiblemente incluye heterociclilamino de 3- a 10- miembros.In this document, "heterocyclylamino" refers to an amino group linked with a "heterocyclyl" defined above. The heterocyclylamino preferably includes 3- to 10-membered heterocyclylamino.
En este documento, "clanoalquilo" se refiere a un grupo en el cual un átomo de hidrógeno arbitrario en un “alquilo” definido anteriormente es sustituido con un grupo ciano. El cianoalquilo preferiblemente incluye ciano(alquilo C1.3).In this document, "clanoalkyl" refers to a group in which an arbitrary hydrogen atom in an "alkyl" defined above is substituted with a cyano group. The cyanoalkyl preferably includes cyano (C1.3 alkyl).
En este documento, "alquilsulfonilo" se refiere a un grupo sulfonilo unido con un “alquilo” definido anteriormente (i.e. alqullo-S02-). El alquilsulfonilo preferiblemente incluye alquilsulfonilo C1.3. Específicamente, el alquilsulfonilo incluye metilsulfonilo, etilsulfonilo, n-propilsulfonilo, y i-propilsulfonilo.In this document, "alkylsulfonyl" refers to a sulfonyl group linked with an "alkyl" defined above (i.e. alkullo-S02-). The alkylsulfonyl preferably includes C1.3 alkylsulfonyl. Specifically, the alkylsulfonyl includes methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, and i-propylsulfonyl.
En este documento, "alquilsulfonilalquilo" se refiere a un grupo en el cual un átomo de hidrógeno arbitrario en un “alquilo” definido anteriormente es sustituido con un "alquilsulfonilo" definido anteriormente. El alquilsulfonilalquilo preferiblemente incluye alquilsulfonilo C1-3 alquilo C1-4 y alquilsulfonilo C1-3 alquilo C2-4.In this document, "alkylsulfonylalkyl" refers to a group in which an arbitrary hydrogen atom in a "alkyl" defined above is substituted with a "alkylsulfonyl" defined above. The alkylsulfonylalkyl preferably includes C1-3 alkylsulfonyl C1-4 alkyl and C1-3 alkylsulfonyl C2-4 alkyl.
Los compuestos de la presente invención y descripción incluyen formas libres y sales farmacéuticamente aceptables del mismo. Tales "sales" incluyen, por ejemplo, sales de ácido inorgánico, sales de ácido orgánico, sales de base inorgánica, sales de base orgánica, y sales de aminoácidos básicos o ácidos.The compounds of the present invention and description include free forms and pharmaceutically acceptable salts thereof. Such "salts" include, for example, salts of inorganic acid, salts of organic acid, salts of inorganic base, salts of organic base, and salts of basic or acidic amino acids.
Las sales de ácido inorgánico preferidas incluyen, por ejemplo, clorhidrato, bromhldrato, sulfato, nitrato y fosfato. Las sales orgánicas preferidas incluyen, por ejemplo, acetato, succinato, fumarato, maleato, tartrato, citrato, lactato, malato, estearato, benzoato, metanosulfonato, y p-toluenosulfonato. Una sal particularmente preferida en la presente invención y descripción es malato.Preferred inorganic acid salts include, for example, hydrochloride, bromhydrate, sulfate, nitrate and phosphate. Preferred organic salts include, for example, acetate, succinate, fumarate, maleate, tartrate, citrate, lactate, malate, stearate, benzoate, methanesulfonate, and p-toluenesulfonate. A particularly preferred salt in the present invention and description is malate.
Las sales de bases inorgánicas preferidas incluyen, por ejemplo, sales de metales alcalinos tales como sales de sodio y sales de potasio; sales de metales alcalinotérreos tales como sales de calcio y sales de magnesio; sales de aluminio; y sales de amonio. Las sales de bases orgánicas preferidas Incluyen, por ejemplo, sales de dietilamina, sales de dietanolamina, sales de meglumina, y sales de N, N-dlbenclletlIendlamlna.Preferred inorganic base salts include, for example, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts; and ammonium salts. Preferred organic base salts include, for example, diethylamine salts, diethanolamine salts, meglumine salts, and salts of N, N-dlbenclletlIendlamlna.
Las sales de aminoácidos ácidos preferidos incluyen, por ejemplo, aspartato y glutamato. Las sales de aminoácidos básicos preferidos incluyen, por ejemplo, sales de arginina, sales de Usina, y sales de ornitina.Preferred acidic amino acid salts include, for example, aspartate and glutamate. Preferred basic amino acid salts include, for example, arginine salts, Usine salts, and ornithine salts.
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Cuando los compuestos de la presente invención/descripción se dejan reposar al ambiente, pueden absorber la humedad para adsorber agua o formar hidratos. Tales hidratos también están Incluidos en las sales de la presente invención/descripción.When the compounds of the present invention / description are allowed to stand in the environment, they can absorb moisture to adsorb water or form hydrates. Such hydrates are also included in the salts of the present invention / description.
Adicionalmente, los compuestos de la presente invención/descripción pueden absorber otros solventes para formar solvatos. Tales solvatos también se incluyen en las sales de la presente invención/descripción.Additionally, the compounds of the present invention / description can absorb other solvents to form solvates. Such solvates are also included in the salts of the present invention / description.
Todos los Isómeros estructuralmente posibles (isómeros geométricos, Isómeros ópticos, estereoisómeros, tautómeros, etc.) de los compuestos de la presente invención y descripción y mezclas de tales isómeros se incluyen en la presente descripción.All structurally possible Isomers (geometric isomers, optical isomers, stereoisomers, tautomers, etc.) of the compounds of the present invention and description and mixtures of such isomers are included in the present description.
Los compuestos de la presente Invención/descripción pueden tener formas cristalinas polimórficas. Todos los citados polimorfos se Incluyen en la presente Invención/descripción.The compounds of the present invention / description may have polymorphic crystalline forms. All such polymorphs are included in the present invention / description.
Adicionalmente, se describen en este documento los profármacos de los compuestos de la presente invención y descripción. Los profármacos se refieren a derivados de los compuestos de la presente invención y descripción, que tienen un grupo químico o metabólicamente degradable, y tras la administración al cuerpo vivo, revierten a los compuestos originales y muestran la eficacia del fármaco original. Los profármacos incluyen complejos no covalentes y sales.Additionally, the prodrugs of the compounds of the present invention and description are described herein. Prodrugs refer to derivatives of the compounds of the present invention and description, which have a chemically or metabolically degradable group, and after administration to the living body, revert to the original compounds and show the efficacy of the original drug. Prodrugs include non-covalent complexes and salts.
Los compuestos de la presente invención/descripción incluyen aquellos en los que uno o más átomos dentro de la molécula han sido reemplazados con isótopos. En este documento, el isótopo se refiere a un átomo que tiene el mismo número atómico (número de protones), pero es diferente en número de masa (suma de protones y neutrones). Los átomos diana que se reemplazan por un isótopo en los compuestos de la presente invención/descripción, incluyen, por ejemplo, átomo de hidrógeno, átomo de carbono, átomo de nitrógeno, átomo de oxígeno, átomo de fósforo, átomo de azufre, átomo de flúor, y átomo de cloro. Sus isótopos incluyen TH, 3H, 13C, 14C, 15N, 170, 180, 31P, 32P, 35S, 18F y 36CI. En particular, los radioisótopos tales como 3H y 14C, que deterioran la emisión de la radiación, son útiles en el estudio de la distribución tisular in vivo etc. de productos farmacéuticos o compuestos. Los isótopos estables no se deterioran, son casi constantes en abundancia, y no emiten radiación. Por esta razón, los isótopos estables pueden ser utilizados con seguridad. Los compuestos de la presente invención/descripción se pueden convertir en compuestos de isótopos-sustituidos de acuerdo con métodos convencionales mediante la sustitución de los reactivos utilizados en la síntesis con reactivos que contienen los isótopos correspondientes.The compounds of the present invention / description include those in which one or more atoms within the molecule have been replaced with isotopes. In this document, the isotope refers to an atom that has the same atomic number (number of protons), but is different in mass number (sum of protons and neutrons). The target atoms that are replaced by an isotope in the compounds of the present invention / description, include, for example, hydrogen atom, carbon atom, nitrogen atom, oxygen atom, phosphorus atom, sulfur atom, atom of fluorine, and chlorine atom. Its isotopes include TH, 3H, 13C, 14C, 15N, 170, 180, 31P, 32P, 35S, 18F and 36CI. In particular, radioisotopes such as 3H and 14C, which impair the emission of radiation, are useful in the study of tissue distribution in vivo etc. of pharmaceutical products or compounds. Stable isotopes do not deteriorate, are almost constant in abundance, and do not emit radiation. For this reason, stable isotopes can be used safely. The compounds of the present invention / description can be converted into isotope-substituted compounds according to conventional methods by replacing the reagents used in the synthesis with reagents containing the corresponding isotopes.
Preferiblemente, los compuestos de la presente descripción o invención, respectivamente, representados por la formula (I) mostrada anteriormente son los siguientes:Preferably, the compounds of the present description or invention, respectively, represented by the formula (I) shown above are the following:
Ri mostrado arriba, preferiblemente representa hidrógeno, hidroxi, halógeno, ciano, nitro, haloalquilo Cm, alquilo Ci. 6, alquenilo C2-6, alquinilo C2.6, cicloalquilo C3.7, arilo C6-io alquilo Cm, -OR5, -NR6R7, -(CRsRsOnZ-i, -C(0)NR12Ri3, - SR14, -SOR-I5, -S02Rie, -NRi7S02Ri8, COOH, arilo C6-io que es opcionalmente sustituido con uno o más grupos independientemente seleccionados del grupo P, heteroarilo de 5- a 10- miembros o heterociclilo de 3- a 10- miembros cada uno de los cuales es opcionalmente sustituido con uno o más grupos independientemente seleccionados del grupo Q, -COR19, -COOR20,- OC(0)R2i, -NR22C(0)R23, -NR24C(S)R2s, -C(S)NR26R27, - SO2NR28R29, -OSO2R3O, -SO3R31, O -S¡(R32)3-Ri shown above preferably represents hydrogen, hydroxy, halogen, cyano, nitro, haloalkyl Cm, Ci alkyl. 6, C2-6 alkenyl, C2.6 alkynyl, C3.7 cycloalkyl, C6-aryl alkyl Cm, -OR5, -NR6R7, - (CRsRsOnZ-i, -C (0) NR12Ri3, - SR14, -SOR-I5 , -S02Rie, -NRi7S02Ri8, COOH, C6-io aryl which is optionally substituted with one or more groups independently selected from the P group, 5- to 10-membered heteroaryl or 3- to 10-membered heterocyclyl each of which is optionally substituted with one or more groups independently selected from group Q, -COR19, -COOR20, - OC (0) R2i, -NR22C (0) R23, -NR24C (S) R2s, -C (S) NR26R27, - SO2NR28R29 , -OSO2R3O, -SO3R31, OR -S¡ (R32) 3-
R1 mostrado arriba, más preferiblemente representa hidrógeno, hidroxi, halógeno, ciano, haloalquilo Cm, alquilo C-m, alquinilo C2.6, cicloalquilo C3.7, arilo C6-10 alquilo Cm, -OR5, -NR6R7, -(CRsRsOnZ-i, -C(0)NRi2Ri3, -SR-m, -SO2R16, - NR-|7S02Ri8, COOH, arilo C6-io que es opcionalmente sustituido con uno o más grupos independientemente seleccionados del grupo P, o heteroarilo de 5- a 10- miembros o heterociclilo de 3- a 10- miembros cada uno de los cuales es opcionalmente sustituido con uno o más grupos independientemente seleccionados del grupo Q. Específicamente, el anterior heteroarilo de 5- a 10- miembros en particular es preferiblemente un grupo imidazolilo, grupo tienilo, grupo piridilo, grupo piridazinilo, o grupo pirazolilo. El anterior heterociclilo de 3- a 10- miembros en particular es preferiblemente un grupo morfolinilo, grupo tetrahidropiridilo, o grupo piperidinilo.R1 shown above, more preferably represents hydrogen, hydroxy, halogen, cyano, haloalkyl Cm, Cm alkyl, C2.6 alkynyl, C3.7 cycloalkyl, C6-10 aryl, Cm, -OR5, -NR6R7, - (CRsRsOnZ-i, -C (0) NRi2Ri3, -SR-m, -SO2R16, - NR- | 7S02Ri8, COOH, C6-io aryl which is optionally substituted with one or more groups independently selected from the group P, or heteroaryl from 5- to 10- 3- or 10-membered heterocyclyl or members each of which is optionally substituted with one or more groups independently selected from group Q. Specifically, the above 5- to 10-membered heteroaryl in particular is preferably an imidazolyl group, group thienyl, pyridyl group, pyridazinyl group, or pyrazolyl group The above 3- to 10-membered heterocyclyl in particular is preferably a morpholinyl group, tetrahydropyridyl group, or piperidinyl group.
R2 mostrado arriba, preferiblemente representa hidrógeno, hidroxi, halógeno, ciano, nitro, haloalquilo Cm, alquilo Ci. 6, alquenilo C2.6, alquinilo C2-6, cicloalquilo C3.7, arilo C6--io alquilo Cm, -ORs, -NReR7, -(CRsRgjnZi, -C(0)NRi2Ri3, - SR14, -SOR15, -S02Ri6, -NR-i7S02Ri8, COOH, arilo C6--io que es opcionalmente sustituido con uno o más grupos independientemente seleccionados del grupo P, heteroarilo de 5- a 10- miembros o heterociclilo de 3- a 10- miembros cada uno de los cuales es opcionalmente sustituido con uno o más grupos independientemente seleccionados del grupo Q, -COR19, -COOR20, -OC(0)R2i, -NR22C(0)R23, -NR24C(S)R25, -C(S)NR26R27, - S02N R28R29, -OS02R3o, -S03R3-i, o -Sí(R32)3.R2 shown above preferably represents hydrogen, hydroxy, halogen, cyano, nitro, haloalkyl Cm, Ci alkyl. 6, C2.6 alkenyl, C2-6 alkynyl, C3.7 cycloalkyl, C6 aryl - io alkyl Cm, -ORs, -NReR7, - (CRsRgjnZi, -C (0) NRi2Ri3, - SR14, -SOR15, -S02Ri6 , -NR-i7S02Ri8, COOH, C6-io aryl which is optionally substituted with one or more groups independently selected from the P group, 5- to 10-membered heteroaryl or 3- to 10-membered heterocyclyl each of which it is optionally substituted with one or more groups independently selected from group Q, -COR19, -COOR20, -OC (0) R2i, -NR22C (0) R23, -NR24C (S) R25, -C (S) NR26R27, - S02N R28R29, -OS02R3o, -S03R3-i, or -Yes (R32) 3.
R2 mostrado arriba, más preferiblemente representa hidrógeno, halógeno, haloalquilo Cm, alquilo C-m, -OR5, arilo C6-10 que es opcionalmente sustituido con uno o más grupos independientemente seleccionados del grupo P, oR2 shown above, more preferably represents hydrogen, halogen, haloalkyl Cm, C-m alkyl, -OR5, C6-10 aryl which is optionally substituted with one or more groups independently selected from the group P, or
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heteroarilo de 5- a 10- miembros que es opcionalmente sustituido con uno o más grupos independientemente seleccionados del grupo Q. Específicamente, este heteroarilo de 5- a 10- miembros en particular es preferiblemente un grupo piridilo.5- to 10-membered heteroaryl which is optionally substituted with one or more groups independently selected from group Q. Specifically, this particular 5- to 10-membered heteroaryl is preferably a pyridyl group.
Ri y R2 mostrado arriba, preferiblemente puede ser tomado junto con los átomos a los cuales se unen para formar heterociclilo de 3- a 10- miembros o heteroarilo de 5- a 10- miembros. El heterociclilo o heteroarilo puede tener un átomo de halógeno como un sustituyente. Específicamente, el heterociclilo de 3- a 10- miembros formado junto con los átomos a los cuales Ri y R2 se unen, en particular es preferiblemente un grupo dioxolanilo o grupo dioxanilo.Ri and R2 shown above can preferably be taken together with the atoms to which they bind to form 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl. The heterocyclyl or heteroaryl may have a halogen atom as a substituent. Specifically, the 3- to 10-membered heterocyclyl formed together with the atoms to which Ri and R2 bind, in particular is preferably a dioxolanyl group or dioxanyl group.
R3 mostrado arriba, preferiblemente representa hidrógeno, alquilo Ci_5, arilo C6-io alquilo C-m, o haloalquilo Ci_4, más preferiblemente hidrógeno, alquilo C1.4, arilo C6-io alquilo C1.4, o perfluoroalquilo C1.3, y en particular preferiblemente alquilo C1.R3 shown above preferably represents hydrogen, Ci_5 alkyl, C6-aryl-Ci-alkyl, or C__haloalkyl, more preferably hydrogen, C1.4-alkyl, C6-aryl-C1.4-alkyl, or C1.3-perfluoroalkyl, and particularly preferably C1 alkyl.
R4 mostrado arriba, preferiblemente representa hidrógeno, halógeno, alquilo C1-3, haloalquilo C1.4, hidroxi, ciano, nitro, alcoxi C1-4, -(CH2)nZi, -NR6R7, -OR5, -C(0)NRi2Ri3, -SR14, -SOR15, -SO2R16, NR17SO2R18, COOH, -COR19, - COOR20, -OC(0)R2i, -NR22C(0)R23, -NR24C(S)R25,- C(S)NR26R27, -SO2NR28R29, -OSO2R30-SO3R31, o -SÍ(R32)3.R4 shown above preferably represents hydrogen, halogen, C1-3 alkyl, C1.4 haloalkyl, hydroxy, cyano, nitro, C1-4 alkoxy, - (CH2) nZi, -NR6R7, -OR5, -C (0) NRi2Ri3, -SR14, -SOR15, -SO2R16, NR17SO2R18, COOH, -COR19, - COOR20, -OC (0) R2i, -NR22C (0) R23, -NR24C (S) R25, - C (S) NR26R27, -SO2NR28R29, -OSO2R30-SO3R31, or -YES (R32) 3.
R4 mostrado arriba, más preferiblemente representa hidrógeno, halógeno, alquilo C1-3, perfluoroalquilo C1.3, ciano, metanosulfonilo, hidroxilo, alcoxi, o amino, y en particular preferiblemente hidrógeno o halógeno.R4 shown above, more preferably represents hydrogen, halogen, C1-3 alkyl, perfluoroalkyl C1.3, cyano, methanesulfonyl, hydroxyl, alkoxy, or amino, and in particular preferably hydrogen or halogen.
El anillo A es indol o pirrol.Ring A is indole or pyrrole.
Rs mostrado arriba, preferiblemente representa alquilo Ci_5, cicloalquilo C3.7, cicloalquilo C3.7 alquilo Ci_3, alquenilo C2-6, alquinilo C2-6, haloalquilo C1-4, alcoxi C1.3 alquilo Cm, alcoxi C1.3 alcoxi C1.4 alquilo Cm, aminoalquilo C1.4, alquilamino C1-4 alquilo C1-4, di(alquilo C-Mjamino alquilo C1-4, arilo C6-10, arilo C6-10 alquilo C1-3, o heterociclilo de 3- a 10- miembros alquilo C1-3, heterociclilo de 3- a 10- miembros, heteroarilo de 5- a 10- miembros, o heteroarilo de 5- a 10- miembros alquilo C1-3, cada uno de los cuales es opcionalmente sustituido con uno o más grupos independientemente seleccionados del grupo Q, monohidroxialquilo C-i-e, dihidroxialquilo C-i-e, o trihidroxialquilo C-m.Rs shown above preferably represents Ci_5 alkyl, C3.7 cycloalkyl, C3.7 cycloalkyl Ci_3 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1.3 alkoxy Cm, C1.3 alkoxy C1 alkoxy. 4 Cm alkyl, C1.4 aminoalkyl, C1-4 alkylamino C1-4 alkyl, di (C-Mjamino alkyl C1-4 alkyl, C6-10 aryl, C6-10 aryl C1-3 alkyl, or 3- to 10 heterocyclyl - C1-3 alkyl members, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or 5- to 10-heteroaryl C1-3 alkyl members, each of which is optionally substituted with one or more groups independently selected from group Q, Cie monohydroxyalkyl, Cie dihydroxyalkyl, or trihydroxyalkyl Cm.
Rs mostrado arriba, más preferiblemente representa alquilo C1.5, cicloalquilo C3.7 alquilo C1-3, haloalquilo C1.4, alcoxi C1.3 alquilo C1.4, arilo Ce-io, arilo Ce-io alquilo Ci.3, o heterociclilo de 3- a 10- miembros alquilo Ci.3 o heterociclilo de 3- a 10- miembros cada uno de los cuales es opcionalmente sustituido con uno o más grupos independientemente seleccionados del grupo Q. Específicamente, el anterior heterociclilalquilo de 3- a 10- miembros en particular es preferiblemente un grupo piperaziniletilo, grupo oxetanilmetilo, o grupo morfolinil etilo. El anterior heterociclilo de 3- a 10- miembros en particular es preferiblemente un grupo oxetanil o grupo tetrahidropiranilo.Rs shown above, more preferably represents C1.5 alkyl, C3.7 cycloalkyl C1-3 alkyl, C1.4 haloalkyl, C1.3 alkoxy C1.4 alkyl, aryl Ce-io, aryl Ce-io alkyl Ci.3, or 3- to 10-membered heterocyclyl Ci.3 alkyl or 3- to 10-membered heterocyclyl each of which is optionally substituted with one or more groups independently selected from group Q. Specifically, the above 3- to 10 heterocyclyl alkyl - members in particular is preferably a piperazinylethyl group, oxetanylmethyl group, or morpholinyl ethyl group. The above 3- to 10-membered heterocyclyl in particular is preferably an oxetanyl group or tetrahydropyranyl group.
R6 y R7 mostrados arriba, pueden ser iguales o diferentes, y preferiblemente cada uno representa hidrógeno, alquilo C-m, alquenilo C2-6, alquinilo C2-6, haloalquilo C1.4, alcoxi Ci.3 alquilo C2-4, arilo C6-10 alquilo C1.3, heterociclilo de 3- a 10- miembros alquilo Ci_3, heteroarilo de 5- a 10- miembros alquilo Ci.3, monohidroxialquilo Ci.6, dihidroxialquilo Ci.6, trihidroxialquilo Ci.6, heterociclilo de 3- a 10- miembros, aminoalquilo C-m, alquilamino C-m alquilo C-m, di(alquilo C-i_ 4)amino alquilo Cm, o c¡ano(alqu¡lo Ci_3).R6 and R7 shown above, may be the same or different, and preferably each represents hydrogen, Cm alkyl, C2-6 alkenyl, C2-6 alkynyl, C1.4 haloalkyl, Ci.3 alkoxyC2-4 alkyl, C6-10 aryl C1.3 alkyl, 3- to 10-membered heterocyclyl Ci_3 alkyl, 5- to 10-membered heteroaryl Ci.3 alkyl, Ci.6 monohydroxyalkyl, Ci.6 dihydroxyalkyl, Ci.6 trihydroxyalkyl, 3- to 10 heterocyclyl - members, aminoalkyl Cm, alkylamino Cm alkyl Cm, di (C-i_ 4 alkyl) amino alkyl Cm, ocean (Ci_3 alkyl).
R6 y R7 mostrados arriba, más preferiblemente cada uno independientemente representa hidrógeno, alcoxi Ci_3 alquilo Cm, heterociclilo de 3- a 10- miembros alquilo C1-3, heteroarilo de 5- a 10- miembros alquilo C1-3, o dihidroxialquilo Cm. Específicamente, el heterociclilalquilo de 3- a 10- miembros en particular es preferiblemente un grupo morfoliniletilo, y el heteroarilalquilo de 5- a 10- miembros en particular es preferiblemente un grupo piridiletilo.R6 and R7 shown above, more preferably each independently represents hydrogen, Ci_3 alkoxyC1 alkyl, 3- to 10-membered heterocyclyl C1-3 alkyl, 5- to 10-membered heteroaryl C1-3 alkyl, or dihydroxyalkyl Cm. Specifically, the 3- to 10-membered heterocyclylalkyl in particular is preferably a morpholinylethyl group, and the 5- to 10-membered heteroarylalkyl in particular is preferably a pyridylethyl group.
Alternativamente, R6 y R7 mostrados arriba, preferiblemente pueden ser tomados junto con los átomos de nitrógeno a los cuales se unen para formar un heterociclilo de 3- a 10- miembros o heteroarilo de 5- a 10- miembros.Alternatively, R6 and R7 shown above may preferably be taken together with the nitrogen atoms to which they are attached to form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl.
"n" mostrado arriba, representa número entero desde 1 a 3. Preferiblemente, n es 1."n" shown above represents an integer from 1 to 3. Preferably, n is 1.
R8 y R9 mostrados arriba, preferiblemente pueden ser iguales o diferentes, y cada uno representa hidrógeno, alquilo Cm, o halógeno, y más preferiblemente hidrógeno.R8 and R9 shown above, may preferably be the same or different, and each represents hydrogen, Cm alkyl, or halogen, and more preferably hydrogen.
Alternativamente, Rs y R9 mostrados arriba, preferiblemente pueden ser tomados junto con los átomos de carbono a los cuales se unen para formar un anillo alicíclico.Alternatively, Rs and R9 shown above may preferably be taken together with the carbon atoms to which they are attached to form an alicyclic ring.
Z1 mostrado arriba, preferiblemente representa hidrógeno, NR10R11, -OH, o heterociclilo de 3- a 10- miembros o heteroarilo de 5- a 10- miembros cada uno de los cuales es opcionalmente sustituido con uno o más grupos independientemente seleccionados del grupo Q, más preferiblemente NR10R11 o -OH, o heterociclilo de 3- a 10- miembros que es opcionalmente sustituido con uno o más grupos independientemente seleccionados del grupo Q.Z1 shown above preferably represents hydrogen, NR10R11, -OH, or 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl each of which is optionally substituted with one or more groups independently selected from group Q, more preferably NR10R11 or -OH, or 3- to 10-membered heterocyclyl which is optionally substituted with one or more groups independently selected from group Q.
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Específicamente, el anterior heterociclilo de 3- a 10- miembros en particular es preferiblemente un grupo pirrolidinilo, grupo piperazinilo, grupo piperidinilo, o grupo morfolinilo.Specifically, the above 3- to 10-membered heterocyclyl in particular is preferably a pyrrolidinyl group, piperazinyl group, piperidinyl group, or morpholinyl group.
Río y R11 mostrados arriba, preferiblemente pueden ser iguales o diferentes, y cada uno preferiblemente representa alquilo C-i-4, alquenilo C2-6, alquinilo C2-6, haloalquilo Cm, alcoxi C1.3 alquilo Cm, ciano(alquilo C1.3), o alquilsulfonilo C1.3 alquilo C1-4, más preferiblemente alquilo C1-4, alquinilo C2-6, o alcoxi C1.3 alquilo C2-4.Rio and R11 shown above, may preferably be the same or different, and each preferably represents Ci-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, haloalkyl Cm, C1.3 alkoxy, C1 alkyl, cyano (C1.3 alkyl) , or C1.3 alkylsulfonyl C1-4 alkyl, more preferably C1-4 alkyl, C2-6 alkynyl, or C1.3 alkoxyC2-4 alkyl.
Alternativamente, Rioy R11 mostrado arriba, preferiblemente puede ser tomado junto con los átomos de nitrógeno a los cuales se unen para formar heterociclilo de 3- a 10- miembros o heteroarllo de 5- a 10- miembros.Alternatively, Rioy R11 shown above, can preferably be taken together with the nitrogen atoms to which they bind to form 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl.
R12 y R13 mostrados arriba, preferiblemente pueden ser ¡guales o diferentes, y cada uno representa hidrógeno, alquilo C1.4, alquenilo C2.e, alquinilo C2-6, haloalquilo C1-4, alcoxi C1.3 alquilo C-m, arilo Ce-io, heteroarilo de 5- a 10- miembros, heterociclilo de 3- a 10- miembros, arilo Ce-io alquilo C1-4, heterociclilo de 3- a 10- miembros alquilo C1.3, heteroarllo de 5- a 10- miembros alquilo C1-3, cianojalquilo C1.3), alquilsulfonilo C1.3 alquilo C1.4, o anillo alicíclico de 3- a 10- miembros, más preferiblemente hidrógeno, alquilo C1.4, o haloalquilo Cm-R12 and R13 shown above, may preferably be the same or different, and each represents hydrogen, C1.4 alkyl, C2 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, C1.3 alkoxy Cm alkyl, Ce- aryl io, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclyl, aryl Ce-io C1-4 alkyl, 3- to 10-membered heterocyclyl C1.3 alkyl, 5- to 10-membered heteroaryl C1-3 alkyl, C1.3 cyanojalkyl), C1.3 alkyl sulfonyl C1.4 alkyl, or 3- to 10-membered alicyclic ring, more preferably hydrogen, C1.4 alkyl, or Cm- haloalkyl
Alternativamente, R12 y R13 mostrado arriba, preferiblemente se pueden tomar junto con los átomos de nitrógeno a los cuales se unen para formar un heterociclilo de 3- a 10- miembros o heteroarilo de 5- a 10- miembros cada uno de los cuales es opcionalmente sustituido con uno o más grupos independientemente seleccionados del grupo Q, y en particular preferiblemente heterociclilalquilo de 3- a 10- miembros. Específicamente, son más preferidos el grupo piperazinilo, grupo morfolinilo, grupo pirrolidinilo, y grupo piperidinilo.Alternatively, R12 and R13 shown above, can preferably be taken together with the nitrogen atoms to which they are attached to form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl each of which is optionally substituted with one or more groups independently selected from the group Q, and in particular preferably 3- to 10-membered heterocyclylalkyl. Specifically, the piperazinyl group, morpholinyl group, pyrrolidinyl group, and piperidinyl group are more preferred.
R14 mostrado arriba, preferiblemente representa alquilo C-m, alquenilo C2-6, alquinilo C2-6, haloalquilo C1.4, arilo C6-10 que es opcionalmente sustituido con uno o más grupos independientemente seleccionados del grupo P, o heteroarilo de 5- a 10- miembros o heterociclilo de 3- a 10- miembros cada uno de los cuales es opcionalmente sustituido con uno o más grupos independientemente seleccionados del grupo Q, y más preferiblemente representa alquilo Cm o haloalquilo C1.4.R14 shown above preferably represents Cm alkyl, C2-6 alkenyl, C2-6 alkynyl, C1.4 haloalkyl, C6-10 aryl which is optionally substituted with one or more groups independently selected from the P group, or 5- to 10 heteroaryl - 3- or 10-membered heterocyclyl or members each of which is optionally substituted with one or more groups independently selected from the group Q, and more preferably represents C 1 alkyl or C 1-4 haloalkyl.
R15 mostrado arriba, preferiblemente representa alquilo Ci_4, alquenilo C2-6, alquinilo C2-6, haloalquilo C1.4, arilo C6-io que es opcionalmente sustituido con uno o más grupos independientemente seleccionados del grupo P, o heteroarilo de 5- a 10- miembros o heterociclilo de 3- a 10- miembros cada uno de los cuales es opcionalmente sustituido con uno o más grupos independientemente seleccionados del grupo Q.R15 shown above preferably represents Ci_4 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1.4 haloalkyl, C6-io aryl which is optionally substituted with one or more groups independently selected from the P group, or 5- to 10 heteroaryl - 3- or 10-membered heterocyclyl or members each of which is optionally substituted with one or more groups independently selected from group Q.
R16 mostrado arriba, preferiblemente representa alquilo Cm, alquenilo C2.e, alquinilo C2.6, haloalquilo C-m, arilo C6-io que es opcionalmente sustituido con uno o más grupos independientemente seleccionados del grupo P, o heteroarllo de 5- a 10- miembros o heterociclilo de 3- a 10- miembros cada uno de los cuales es opcionalmente sustituido con uno o más grupos independientemente seleccionados del grupo Q, y más preferiblemente representa alquilo Cm.R16 shown above preferably represents Cm alkyl, C2 alkenyl, C2.6 alkynyl, Cm haloalkyl, C6-io aryl which is optionally substituted with one or more groups independently selected from the P group, or 5- to 10-membered heteroaryl or 3- to 10-membered heterocyclyl each of which is optionally substituted with one or more groups independently selected from the group Q, and more preferably represents C 1 alkyl.
R17 mostrado arriba, preferiblemente representa hidrógeno o alquilo Cm, y más preferiblemente hidrógeno.R17 shown above, preferably represents hydrogen or Cm alkyl, and more preferably hydrogen.
R-is mostrado arriba, preferiblemente representa alquilo C-m, alquenilo C2.e, alquinilo C2.6, haloalquilo Cm, arilo C6-io que es opcionalmente sustituido con uno o más grupos independientemente seleccionados del grupo P, o heteroarllo de 5- a 10- miembros o heterociclilo de 3- a 10- miembros cada uno de los cuales es opcionalmente sustituido con uno o más grupos Independientemente seleccionados del grupo Q, y más preferiblemente representa alquilo Cm.R-is shown above, preferably represents Cm alkyl, C2 alkenyl, C2.6 alkynyl, Cm haloalkyl, C6-io aryl which is optionally substituted with one or more groups independently selected from the P group, or heteroaryl from 5- to 10 - 3- or 10-membered heterocyclyl or members each of which is optionally substituted with one or more groups independently selected from the group Q, and more preferably represents C 1 alkyl.
R19 mostrado arriba, preferiblemente representa hidrógeno, alquilo Cm, clcloalquilo C3.7, haloalquilo Cm, arilo Ce-io, o heteroarllo de 5- a 10- miembros o heterociclilo de 3- a 10- miembros cada uno de los cuales es opclonalmente sustituido con uno o más grupos independientemente seleccionados del grupo Q, y más preferiblemente representa hidrógeno, o heteroarilo de 5- a 10- miembros o heterociclilo de 3- a 10- miembros cada uno de los cuales es opclonalmente sustituido con uno o más grupos independientemente seleccionados del grupo Q. Específicamente, este heterociclilo de 3- a 10- miembros más preferiblemente es un grupo piperazinilo, grupo morfolinilo, grupo pirrolidinilo, o grupo piperidinilo.R19 shown above preferably represents hydrogen, Cm-alkyl, C3.7-cycloalkyl, Cm-haloalkyl, Ce-io aryl, or 5- to 10-membered heteroaryl or 3- to 10-membered heterocyclyl each of which is opclonally substituted with one or more groups independently selected from group Q, and more preferably represents hydrogen, or 5- to 10-membered heteroaryl or 3- to 10-membered heterocyclyl each of which is opclonally substituted with one or more independently selected groups from group Q. Specifically, this 3- to 10-membered heterocyclyl is more preferably a piperazinyl group, morpholinyl group, pyrrolidinyl group, or piperidinyl group.
R20 mostrado arriba, preferiblemente representa alquilo Cm, clcloalquilo C3.7, haloalquilo Cm, arilo C6-io, heteroarllo de 5- a 10- miembros, o heterociclilo de 3- a 10- miembros.R20 shown above preferably represents Cm-alkyl, C3.7-cycloalkyl, Cm-haloalkyl, C6-io aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl.
R21 mostrado arriba, preferiblemente representa alquilo Cm, cicloalquilo C3-7, haloalquilo Cm, arilo C6-io, heteroarilo de 5- a 10- miembros, o heterociclilo de 3- a 10- miembros.R21 shown above preferably represents Cm alkyl, C 3-7 cycloalkyl, Cm haloalkyl, C6-io aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl.
R22 mostrado arriba, preferiblemente representa hidrógeno, alquilo Cm, o haloalquilo Cm.R22 shown above preferably represents hydrogen, Cm alkyl, or Haloalkyl Cm.
R23 mostrado arriba, preferiblemente representa hidrógeno, alquilo Cm, cicloalquilo C3-7, haloalquilo Cm, arilo C6-10, heteroarilo de 5- a 10- miembros, o heterociclilo de 3- a 10- miembros.R23 shown above preferably represents hydrogen, Cm alkyl, C3-7 cycloalkyl, Haloalkyl Cm, C6-10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl.
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45Four. Five
R24 mostrado arriba, preferiblemente representa hidrógeno, alquilo C1.4, o haloalquilo C1-4.R24 shown above preferably represents hydrogen, C1.4 alkyl, or C1-4 haloalkyl.
R25 mostrado arriba, preferiblemente representa alquilo C1-4, cicloalqullo C3-7, haloalquilo C1-4, arilo Ce-io, heteroarilo de 5- a 10- miembros, o heterociclilo de 3- a 10- miembros.R25 shown above preferably represents C1-4 alkyl, C3-7 cycloalkyl, C1-4 haloalkyl, Ce-io aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl.
R26 y R27 mostrados arriba, preferiblemente pueden ser iguales o diferentes, y cada uno representa hidrógeno, alquilo C1.4, alquenilo C2-e, alqulnllo C2-6, haloalquilo C1.4, alcoxl C1.3 alquilo C1.4, arilo C6-io, heteroarilo de 5- a 10- miembros, heterociclilo de 3- a 10- miembros, arilo C6-io alquilo C1.4, heterociclilo de 3- a 10- miembros alquilo C1.3, heteroarilo de 5- a 10- miembros alquilo Ci_3, ciano(alquilo C1.3), alqullsulfonilo C1.3 alquilo Ci_4, o anillo alicíclico de 3- a 10- miembros.R26 and R27 shown above, preferably may be the same or different, and each represents hydrogen, C1.4 alkyl, C2-e alkenyl, C2-6 alkyl, C1.4 haloalkyl, C1.3 alkoxy C1.3 C1.4 alkyl, C6 aryl -io, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclyl, C6-aryl-C 1-4 alkyl, 3- to 10-membered heterocyclyl, C1.3 alkyl, 5- to 10- heteroaryl members Ci_3 alkyl, cyano (C1.3 alkyl), C1.3 alkylsulfonyl Ci_4 alkyl, or 3- to 10-membered alicyclic ring.
Alternativamente, R26 y R27 mostrados arriba, preferiblemente pueden ser tomados junto con los átomos de nitrógeno a los cuales se unen para formar un heterociclilo de 3- a 10- miembros o heteroarilo de 5- a 10- miembros.Alternatively, R26 and R27 shown above, can preferably be taken together with the nitrogen atoms to which they are attached to form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl.
R28 y R29 mostrados arriba, preferiblemente pueden ser iguales o diferentes, y cada uno representa hidrógeno, alquilo C1.4, alquenilo C2-6, alqulnllo C2-6, haloalquilo Ci_4, alcoxi C1.3 alquilo C1.4, arilo C6-io, heteroarilo de 5- a 10- miembros, heterociclilo de 3- a 10- miembros, arilo C6-io alquilo C1.4, heterociclilo de 3- a 10- miembros alquilo C1.3, heteroarilo de 5- a 10- miembros alquilo C1-3, cianojalquilo C1-3), alqullsulfonilo C1-3 alquilo C1.4, o anillo alicíclico de 3- a 10- miembros.R28 and R29 shown above, may preferably be the same or different, and each represents hydrogen, C1.4 alkyl, C2-6 alkenyl, C2-6 alkenyl, C__4 haloalkyl, C1.3 alkoxy C1.4 alkyl, C6-io aryl , 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclyl, C6-yl C1-4 alkyl, 3- to 10-membered C1.3 alkyl heterocyclyl, 5- to 10-membered alkyl heteroaryl C1-3, C1-3 cyanojalkyl), C1-3 alkylsulfonyl C1.4 alkyl, or 3- to 10-membered alicyclic ring.
Alternativamente, R2s y R29 mostrados arriba, preferiblemente se pueden tomar junto con los átomos de nitrógeno a los cuales se unen para formar un heterociclilo de 3- a 10- miembros o heteroarilo de 5- a 10- miembros.Alternatively, R2s and R29 shown above may preferably be taken together with the nitrogen atoms to which they are attached to form a 3- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl.
R30 mostrado arriba, preferiblemente representa alquilo Ci_4, clcloalquilo C3-7, haloalquilo C1.4, arilo C6-10, heteroarilo de 5- a 10- miembros, o heterociclilo de 3- a 10- miembros.R30 shown above preferably represents C 1-4 alkyl, C 3-7 cycloalkyl, C 1-4 haloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl.
R31 mostrado arriba, preferiblemente representa alquilo C1-4, clcloalquilo C3-7, haloalquilo C1.4, arilo C6.10, heteroarilo de 5- a 10- miembros, o heterociclilo de 3- a 10- miembros.R31 shown above preferably represents C1-4 alkyl, C3-7 cycloalkyl, C1.4 haloalkyl, C6.10 aryl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocyclyl.
R32 mostrado arriba, preferiblemente representa alquilo Ci_4, o arilo Ce-io-R32 shown above, preferably represents Ci_4 alkyl, or Ce-io- aryl
Los sustituyentes preferidos incluidos en el grupo P definido anteriormente son halógeno, alquilo C1.4, haloalquilo Ci_ 4, -OH, alcoxi C1-3, haloalcoxi C1.3, heterociclilamino de 3- a 10- miembros, -SO2R, -CN, -N02, y heterociclilo de 3- a 10- miembros; y más preferiblemente halógeno, haloalquilo C-m, alcoxl C1.3, haloalcoxi C1-3, y heterociclilo de 3- a 10- miembros. Específicamente, este heterociclilo de 3- a 10- miembros en particular es preferiblemente un grupo morfolinilo.Preferred substituents included in the group P defined above are halogen, C1.4 alkyl, Ci_4 haloalkyl, -OH, C1-3 alkoxy, C1.3 haloalkoxy, 3- to 10-membered heterocyclylamino, -SO2R, -CN, -N02, and 3- to 10-membered heterocyclyl; and more preferably halogen, C-m haloalkyl, C1.3 alkoxy, C1-3 haloalkoxy, and 3- to 10-membered heterocyclyl. Specifically, this 3- to 10-membered heterocyclyl in particular is preferably a morpholinyl group.
Los sustituyentes preferidos incluidos en el grupo Q definido anteriormente son halógeno, alquilo Ci_4, haloalquilo C-i. 4, -OH, alcoxi C1-3, monohidroxialquilo Ci-e, dihidroxialquilo Ci_6, trihidroxialquilo Ci.e , heterociclilamino de 3- a 10- miembros, -S02R, -CN, -NO2, clcloalquilo C3.7, -COR19, y heterociclilo de 3- a 10- miembros que es opcionalmente sustituido con alquilo C1.4; y más preferiblemente halógeno, alquilo C1.4, haloalquilo Ci_4, -OH, alcoxi C1.3,Preferred substituents included in the group Q defined above are halogen, Ci_4 alkyl, C-i haloalkyl. 4, -OH, C1-3 alkoxy, Ci-e monohydroxyalkyl, Ci_6 dihydroxyalkyl, Ci.e trihydroxyalkyl, 3- to 10-membered heterocyclylamino, -S02R, -CN, -NO2, C3.7 cycloalkyl, and -COR19, and 3- to 10-membered heterocyclyl which is optionally substituted with C1.4 alkyl; and more preferably halogen, C1.4 alkyl, Ci_4 haloalkyl, -OH, C1.3 alkoxy,
monohidroxialquilo Ci.e, -S02Ri6, cicloalquilo C3.7, -COR19, y heterociclilo de 3- a 10- miembros que esCi.e monohydroxyalkyl, -S02Ri6, C3.7 cycloalkyl, -COR19, and 3- to 10-membered heterocyclyl which is
opcionalmente sustituido con alquilo C1.4. Específicamente, este heterociclilo de 3- a 10- miembros másoptionally substituted with C1.4 alkyl. Specifically, this 3- to 10-membered heterocyclyl
preferiblemente es un grupo piperazinilo, grupo piperidinilo, o grupo morfolinilo.preferably it is a piperazinyl group, piperidinyl group, or morpholinyl group.
En los compuestos de la invención preferidos descritos anteriormente, representados por la formula (I) mostrada anteriormente, R4 representa hidrógeno, halógeno, alquilo C1-3, perfluoroalquilo C1-3, ciano, metanosulfonilo,In the preferred compounds of the invention described above, represented by the formula (I) shown above, R4 represents hydrogen, halogen, C1-3 alkyl, perfluoroalkyl C1-3, cyano, methanesulfonyl,
hidroxilo, alcoxi, o amino;hydroxyl, alkoxy, or amino;
A representa indol o pirrol;A represents indole or pyrrole;
el citado compuesto representado por la fórmula (I) general no incluye la [5-amino-1-(2-metil-1H-bencimidazol-5-¡l)- 1 H-pirazol-4-il]-[5-(4-trifluorometil-fenil)-1 H-indol-2-il]-metanona; y cicloalquilo se refiere a un grupo hidrocarburo alifático monovalente cíclico saturado o parcialmente saturado.The said compound represented by the general formula (I) does not include [5-amino-1- (2-methyl-1 H -benzimidazol-5-l) -1 H -pyrazol-4-yl] - [5- ( 4-trifluoromethyl-phenyl) -1 H-indol-2-yl] -methanone; and cycloalkyl refers to a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group.
Específicamente, los compuestos de la presente descripción o invención, respectivamente, incluyen, por ejemplo:Specifically, the compounds of the present description or invention, respectively, include, for example:
(1) [5-am¡no-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-¡l]-(1H-¡ndol-2-il)-metanona;(1) [5-amine-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (1 H -ENDOL-2-yl) -methanone;
(2) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-(6-pirrolidin-1 -ilmetil-1 H-ind ol-2-il)-metanona;(2) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (6-pyrrolidin-1-ylmethyl-1 H-ind ol- 2-yl) -methanone;
(3) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-(4-hidroxi-piperidin-1 -ilmetil)-1 H-indol-2-il]-metanona;(3) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6- (4-hydroxy-piperidin-1-methylmethyl) - 1 H-indole-2-yl] -methanone;
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(4) [5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-(1H-pirrolo[3,2-c]piridin-2-il)-metanona;(4) [5-amino-1- (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-l] - (1 H -pyrrolo [3,2- c] pyridin-2-yl) -methanone;
(5) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-(6-piperaz¡n-1-ilmetil-1H-ind ol-2-¡l)-metanona;(5) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-l] - (6-piperazine) 1-ylmethyl-1H-ind ol-2-l) -methanone;
(6) [5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-[6-(2-morfol¡n-4-il-etoxi)-1 H-indol-2-¡l]-metanona;(6) [5-amino-1- (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-l] - [6- (2-morphol) -4-yl-ethoxy) -1 H-indole-2-l] -methanone;
(7) [5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-[6-(tetrah¡dro-p¡ran-4-iloxi)-1 H-indol-2-¡l]-metanona;(7) [5-amino-1- (2-methyl-1H-benzyldazol-5-l) -1H-prazol-4-l] - [6- (tetrahydro) -p¡ran-4-yloxy) -1 H-indole-2-¡l] -methanone;
(8) [5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(4-cloro-1 H-¡ndol-2-il)-metanona;(8) [5-Amino-1- (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-l] - (4-chloro-1 H -¡Ndol-2-yl) -methanone;
(9) [5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(5-bromo-1H-¡ndol-2-¡l)-metanona;(9) [5-amino-1- (2-methyl-1H-benzyldazol-5-l) -1H-p.razole-4-l] - (5-bromo-1H- Ndol-2-¡l) -methanone;
(10) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1 H-pirazol-4-il]-(4-yodo-1 H-indol-2-il)-metanona;(10) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H-pyrazol-4-yl] - (4-iodo-1 H-indol-2-yl) -methanone ;
(11) 2-[5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-p¡razol-4-carbonil]-1H-indol-5-carbon¡tr¡lo;(11) 2- [5-Amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-carbonyl] -1 H -indole-5-carbonyl;
(12) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-p¡razol-4-¡l]-(6-bromo-5-fluoro-1H-¡ndol-2-y 1)-metanona;(12) [5-am-no-1- (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-l] - (6-bromo-5 -fluoro-1H-¡ndol-2-y 1) -methanone;
(13) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-(5-et¡nil-1 H-indol-2-il)-metanona;(13) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (5-ethynyl-1 H-indole-2-yl ) -methanone;
(14) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-(2-fluoro-fenil)-1 H-indol-2 -il]-metanona;(14) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6- (2-fluoro-phenyl) -1 H-indole -2-yl] -methanone;
(15) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-(3-fluoro-fen¡l)-1 H-indol-2 -il]-metanona;(15) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6- (3-fluoro-phenol) -1 H -indole-2-yl] -methanone;
(16) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-M]-[6-(4-fluoro-fenil)-1 H-indol-2 -il]-metanona;(16) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-M] - [6- (4-fluoro-phenyl) -1 H-indole -2-yl] -methanone;
(17) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-(2-cloro-fenil)-1 H-indol-2 -il]-metanona;(17) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6- (2-chloro-phenyl) -1 H-indole -2-yl] -methanone;
(18) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-p¡razol-4-¡l]-[6-(3-cloro-fen¡l)-1 H-indol-2 -il]-metanona;(18) [5-am-1-1 (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-l] - [6- (3- chloro-phenol) -1 H-indole-2-yl] -methanone;
(19) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(4-cloro-fenil)-1 H-indol-2 -il]-metanona;(19) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6- (4-chloro-phenyl) -1 H-indole-2 -il] -methanone;
(20) [5-amino-1-(2-metil-1H-bencimidazol-5-¡l)-1H-p¡razol-4-il]-[6-(2-trifluorometil-fenil)-1 H-indol-2-il]-metanona;(20) [5-amino-1- (2-methyl-1H-benzimidazol-5-l) -1H-p¡razol-4-yl] - [6- (2-trifluoromethyl-phenyl) -1 H- indole-2-yl] -methanone;
(21) [5-amino-1-(2-metil-1H-bencimidazol-5-¡l)-1H-p¡razol-4-il]-[6-(3-trifluorometil-fenil)-1 H-indol-2-il]-metanona;(21) [5-amino-1- (2-methyl-1H-benzimidazol-5-l) -1H-p¡razol-4-yl] - [6- (3-trifluoromethyl-phenyl) -1 H- indole-2-yl] -methanone;
(22) [5-amino-1-(2-metil-1H-bencimidazol-5-¡l)-1H-p¡razol-4-il]-[6-(4-trifluorometil-fenil)-1 H-indol-2-il]-metanona;(22) [5-Amino-1- (2-methyl-1H-benzimidazol-5-1) -1H-p¡razol-4-yl] - [6- (4-trifluoromethyl-phenyl) -1 H- indole-2-yl] -methanone;
(23) [5-amino-1-(2-metil-1H-bencimidazol-5-ll)-1H-p¡razol-4-il]-(4-bromo-1H-indol-2-il)-metanona;(23) [5-amino-1- (2-methyl-1H-benzimidazol-5-ll) -1H-p¡razol-4-yl] - (4-bromo-1H-indole-2-yl) -methanone ;
(24) [5-amino-1-(2-metil-1H-bencimidazol-5-¡l)-1H-p¡razol-4-il]-[6-(3-fluoro-piridin-2-il)-1H-in dol-2-il]-metanona;(24) [5-amino-1- (2-methyl-1H-benzimidazol-5-l) -1H-p¡razol-4-yl] - [6- (3-fluoro-pyridin-2-yl) -1H-in dol-2-yl] -methanone;
(25) [5-amino-1-(2-metil-1H-bencimidazol-5-ll)-1H-p¡razol-4-il]-(6-metil-1H-indol-2-il)-metanona;(25) [5-amino-1- (2-methyl-1H-benzimidazol-5-ll) -1H-p¡razol-4-yl] - (6-methyl-1H-indole-2-yl) -methanone ;
(26) [5-amlno-l-(2-metil-1 H-bencimidazol-5-ll)-1 H-p¡razol-4-il]-[5-(4,4-difluoro-piperidina-1-carbonll)-1 H-Indol- 2-II]- metanona;(26) [5-amlno-l- (2-methyl-1 H-benzimidazol-5-ll) -1 Hp¡razol-4-yl] - [5- (4,4-difluoro-piperidine-1-carbonll ) -1 H-Indol-2-II] - methanone;
(27) [5-am¡no-1-(2-metil-1H-bencimidazol-5-¡l)-1H-p¡razol-4-il]-[5-(3,3-difluoro-piperidina-1-carbonll)-1 H-Indol- 2-il]- metanona;(27) [5-amine-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H-prazol-4-yl] - [5- (3,3-difluoro-piperidine- 1-carbonll) -1 H-Indol-2-yl] -methanone;
(28) (2,2,2-trlfluoro-etil)-amida del ácido 2-[5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-carbonil]-1H-indol- 5-carboxílico;(28) 2- [5-Amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-carbonyl] - (2,2,2-trlfluoro-ethyl) -amide 1H-indole-5-carboxylic;
(29) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(5-trifluorometil-piridin-2-il)-1H-indol-2-il]-metanona;(29) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [6- (5-trifluoromethyl-pyridin-2-yl) -1H- indole-2-yl] -methanone;
(30) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(6-trifluorometil-piridin-2-il)-1H-indol-2-il]-metanona;(30) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [6- (6-trifluoromethyl-pyridin-2-yl) -1H- indole-2-yl] -methanone;
(31) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(5-cloro-piridin-2-il)-1H-in dol-2-il]-metanona;(31) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [6- (5-chloro-pyridin-2-yl) -1H- in dol-2-il] -methanone;
(32) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-(4-metil-piridin-2-il)-1 H-indol-2-il] metanona;(32) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6- (4-methyl-pyridin-2-yl) - 1 H-indole-2-yl] methanone;
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(33) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-¡l]-[6-(3-cloro-4-fluoro-fenil)-1 H-indol-2-¡l]-metanona;(33) [5-am-1-1 (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-l] - [6- (3-chloro- 4-fluoro-phenyl) -1 H-indole-2-l] -methanone;
(34) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-¡l]-[6-(3-trifluoromet¡l-p¡ridin-2-¡l)-1H-¡ndol-2-¡l]-metanona;(34) [5-am-1-1 (2-methyl-1H-benzyldazol-5-yl) -1H-pyrazol-4-l] - [6- (3-trifluoromet) lp¡ridin-2-¡l) -1H-¡ndol-2-¡l] -methanone;
(35) [5-am¡no-1-(2-met¡l-1 H-bencim¡dazol-5-il)-1 H-pirazol-4-¡l]-[6-(4-trifluorometil-piridin-2-¡l)-1 H-indol-2-¡l] metanona;(35) [5-amine-1- (2-methyl-1 H-benzimdazol-5-yl) -1 H -pyrazol-4-l] - [6- (4-trifluoromethyl- pyridin-2-1) -1 H-indole-2-1] methanone;
(36) [5-am¡no-1-(6-fluoro-2-met¡l-1H-benc¡midazol-5-il)-1H-p¡razol-4-il]-(1H-indol-2-¡l)-metanona;(36) [5-amine-1- (6-fluoro-2-methyl-1H-benzylmidazol-5-yl) -1H-p¡razol-4-yl] - (1H-indole- 2-¡) -methanone;
(37) ácido 2-[5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-carbonil]-1H-indol-6-carboxílico;(37) 2- [5-Amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-carbonyl] -1 H -indole-6-carboxylic acid;
(38) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(6-hidroximetil-1H-indol-2-il)-metanona;(38) [5-Amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (6-hydroxymethyl-1 H -indole-2-yl) -methanone;
(39) [5-am¡no-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-{6-[2-(4-metil-piperazin-1-il)-etoxi]-1H-indol- 2-il}-(39) [5-amine-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - {6- [2- (4-methyl-piperazin-1- il) -ethoxy] -1H-indole-2-yl} -
metanona;methanone;
(40) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(3-metil-oxetan-3-ilmetoxi)-1H-indol-2-il]-metanona;(40) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [6- (3-methyl-oxetan-3-ylmethoxy) -1H- indole-2-yl] -methanone;
(41) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(3-fluoro-piperidin-1-ilmetil)-1H-indol-2-il]-metanona;(41) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [6- (3-fluoro-piperidin-1-ylmethyl) -1H- indole-2-yl] -methanone;
(42) [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-(6-{[bis(2-metoxi-etil)-amin o]-metil}-1 H-indol- 2-il)- metanona;(42) [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - (6 - {[bis (2-methoxy-ethyl) -amin o] -methyl} -1 H-indole-2-yl) -methanone;
(43) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-{6-[(metil-prop-2-inil-amino) -metil]-1 H-indol- 2-il}-(43) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - {6 - [(methyl-prop-2-inyl-amino) -methyl ] -1 H-indole-2-yl} -
metanona;methanone;
(44) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(3,3-difluoro-pirrolidin-1-il metil)-1 H-indol 2-il]- metanona;(44) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6- (3,3-difluoro-pyrrolidin-1-yl methyl) -1 H-indole 2-yl] - methanone;
(45) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(2,5-dimetil-pirrolidin-1-il metil)-1 H-indol- 2-il]-(45) [5-Amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6- (2,5-dimethyl-pyrrolidin-1-yl methyl) -1 H-indole-2-yl] -
metanona;methanone;
(46) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(3,3-difluoro-piperidin-1-ilmetil)-1 H-indol- 2-il]-(46) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6- (3,3-difluoro-piperidin-1-ylmethyl) - 1 H-indole-2-yl] -
metanona;methanone;
(47) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-((S)-3-metil-morfolin-4-il metil)-1 H-indol- 2-il]-(47) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [6 - ((S) -3-methyl-morpholin-4-yl methyl) -1 H-indole-2-yl] -
metanona;methanone;
(48) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(6-bromo-1H-indol-2-il)-metanona;(48) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (6-bromo-1 H -indole-2-yl) -methanone;
(49) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5-yodo-1H-indol-2-il)-metanona;(49) [5-Amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (5-iodo-1 H -indole-2-yl) -methanone;
(50) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(1H-pirrolo[3,2-b]piridin-2-il)-metanona;(50) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (1 H -pyrrolo [3,2-b] pyridin-2-yl) -metanone;
(51) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5-bromo-6-trifluorometil-1H-indol-2-il)-metanona;(51) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (5-bromo-6-trifluoromethyl-1H-indole-2-yl) -metanone;
(52) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(6-yodo-1H-indol-2-il)-metanona;(52) [5-Amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (6-iodo-1 H -indole-2-yl) -methanone;
(53) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(4-metil-1H-indol-2-il)-metanona;(53) [5-Amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (4-methyl-1 H -indole-2-yl) -methanone;
(54) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(4-isopropil-1H-indol-2-il)-metanona;(54) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (4-isopropyl-1 H -indole-2-yl) -methanone;
(55) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[5-(2-fluoro-fenil)-1H-indol-2 -il]-metanona;(55) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [5- (2-fluoro-phenyl) -1H-indole-2 - il] -methanone;
(56) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5-bencil-1H-indol-2-il)-metanona;(56) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (5-benzyl-1 H -indole-2-yl) -methanone;
(57) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[5-(2-trifluorometil-fenil)-1 H-indol-2-il]-metanona;(57) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [5- (2-trifluoromethyl-phenyl) -1 H-indole-2 -il] -methanone;
(58) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[5-(3-fluorofenil)-1H-indol-2-il]-metanona;(58) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [5- (3-fluorophenyl) -1H-indole-2-yl] -metanone;
(59) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[5-(3-trifluorometil-fenil)-1 H-indol-2-il]-metanona;(59) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [5- (3-trifluoromethyl-phenyl) -1 H-indole-2 -il] -methanone;
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(60) [5-am¡no-1-(2-metil-1H-benc¡midazol-5-¡l)-1H-p¡razol-4-¡l]-(4-et¡n¡l-1H-¡ndol-2-¡l)-metanona;(60) [5-am-1-1 (2-methyl-1 H -benzimidazol-5-1) -1 H-p¡razol-4-1] - (4-et-n-1) 1H-¡ndol-2-¡l) -methanone;
(61) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-(5H-[1,3]dioxolo[4,5-f]indol-6-il)-metanona;(61) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - (5H- [1,3] dioxolo [4,5-f ] indole-6-yl) -methanone;
(62) [5-am¡no-1-(7-fluoro-2-metil-1H-bencimidazol-5-¡l)-1H-p¡razol-4-il]-(1H-indol-2-¡l)-metanona;(62) [5-amine-1- (7-fluoro-2-methyl-1H-benzimidazol-5-yl) -1H-p¡razol-4-yl] - (1H-indole-2-¡ l) -methanone;
(63) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-p¡razol-4-¡l]-[5-(4-trifluoromet¡l-fen¡l)-1 H-indol-2-il]-metanona;(63) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-p¡razol-4-¡] - [5- (4-trifluoromethl-fen) -1 H-indole-2-yl] -methanone;
(64) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-p¡razol-4-¡l]-(5-butoxi-1H-indol-2-¡l)-metanona;(64) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-p¡razol-4-¡1] - (5-butoxy-1H-indole-2-¡1) -metanone;
(65) [5-amino-1-(2-metil-1H-bencimidazol-5-¡l)-1H-p¡razol-4-¡l]-[5-(1-metil-piper¡d¡n-4-¡l)-1H -indol-2-il] metanona;(65) [5-amino-1- (2-methyl-1H-benzimidazol-5-l) -1H-p¡razol-4-l] - [5- (1-methyl-piper¡d¡n -4-¡1) -1H -indole-2-yl] methanone;
(66) N-{2-[5-amino-1-(2-metil-1H-bencim¡dazol-5-¡l)-1H-p¡razol-4-carbonil]-1H-¡ndol-6-¡l}-metanosulfonamida;(66) N- {2- [5-amino-1- (2-methyl-1H-benzimdadazol-5-¡l) -1H-p¡razol-4-carbonyl] -1H-¡ndol-6- L} -methanesulfonamide;
(67) [5-am¡no-1-(2-metil-1 H-bencimidazol-5-il)-1 H-p¡razol-4-¡l]-[6-(6-morfolin-4-M-p¡r¡din-3-il)-1 H-indol-2-il]-metanona;(67) [5-amine-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hp¡razol-4-¡1] - [6- (6-morpholin-4-Mp¡ rin-3-yl) -1 H-indol-2-yl] -methanone;
(68) [5-am¡no-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(6-but¡l-1H-¡ndol-2-¡l)-metanona;(68) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1H-p.razole-4-l] - (6-butyl) 1H-¡ndol-2-¡l) -methanone;
(69) [5-am¡no-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-[6-(1-met¡l-1H-p¡razol-4-¡l)-1 H-¡ndol-2-il]-metanona;(69) [5-am¡no-1- (2-methyl-1H-benzamidazol-5-l) -1H-p¡razol-4-¡] - [6- (1-met L-1H-p¡razol-4-¡1) -1 H-¡ndol-2-yl] -methanone;
(70) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-[6-(5-metox¡-p¡r¡d¡n-3-¡l)-1H -indol-2-il]-metanona;(70) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-l] - [6- (5-methox ¡-P¡r¡d¡n-3-¡l) -1H-indol-2-yl] -methanone;
(71) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-[6-(2-metox¡-p¡r¡d¡n-3-¡l)-1H -indol-2-¡l]-metanona;(71) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-l] - [6- (2-methox ¡-P¡r¡d¡n-3-¡l) -1H -indole-2-¡l] -methanone;
(72) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-¡l]-(6-c¡cloprop¡l-1H-¡ndol-2-¡l)-metanona;(72) [5-am-1-1 (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-yl] - (6-cyclopropyl) -1H-¡ndol-2-¡l) -methanone;
(73) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-p¡razol-4-¡l]-[6-(2-metox¡-fen¡l)-1H-¡ndo 1-2-¡l]-metanona;(73) [5-am-no-1- (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-l] - [6- (2- metox¡-fen¡l) -1H-¡ndo 1-2-¡l] -methanone;
(74) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-p¡razol-4-¡l]-(6-fen¡l-1H-¡ndol-2-il)-metanona;(74) [5-am-1-1 (2-methyl-1H-benzyldazol-5-yl) -1 H-prazol-4-l] - (6-phenol) -1H-¡ndol-2-yl) -methanone;
(75) [5-amino-1-(2-metil-1H-bencim¡dazol-5-¡l)-1H-p¡razol-4-¡l]-[6-(5-metanosulfonilo-piridin-3 -il)-1 H-indol-2-M]- metanona;(75) [5-Amino-1- (2-methyl-1H-benzimdazol-5-yl) -1 H -pyrazol-4-l] - [6- (5-methanesulfonyl-pyridin-3 -il) -1 H-indole-2-M] - methanone;
(76) [5-amino-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(6-¡soprop¡l-1H-¡ndol-2-il)-metanona;(76) [5-amino-1- (2-methyl-1H-benzyldazol-5-l) -1H-p¡razol-4-l] - (6-sopropl-1H -¡Ndol-2-yl) -methanone;
(77) [5-amino-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(6-piridin-2-¡l-1H-¡ndol-2-¡l)-metanona;(77) [5-Amino-1- (2-methyl-1H-benzyldazol-5-l) -1H-p¡razol-4-l] - (6-pyridin-2-l) -1H-¡ndol-2-¡l) -methanone;
(78) [5-amino-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(5-cicloprop¡l-1H-¡ndol-2-¡l)-metanona;(78) [5-amino-1- (2-methyl-1H-benzyldazol-5-l) -1H-p¡razol-4-l] - (5-cyclopropyl-1H- Ndol-2-¡l) -methanone;
(79) [5-amino-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-(6-piridaz¡n-3-¡l-1H-¡ndol-2-¡l) -metanona;(79) [5-amino-1- (2-methyl-1H-benzimdazol-5-l) -1H-pyrazol-4-l] - (6-pyridaz-n-3-l -1H-¡ndol-2-¡l) -methanone;
(80) [5-am¡no-1-(2-metil-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-¡l]-(5-¡sopropox¡-1H-¡ndol-2-¡l)-metanona;(80) [5-am-1-1 (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-l] - (5-sopropox-1H-¡ ndol-2-¡l) -methanone;
(81) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-¡l]-[5-(2-metox¡-etox¡)-1H-¡ndo 1-2-¡l]-metanona;(81) [5-am-1-1 (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-l] - [5- (2-methox) -etox¡) -1H-¡ndo 1-2-¡l] -methanone;
(82) [5-am¡no-1-(2-met¡l-1H-benc¡midazol-5-il)-1H-pirazol-4-¡l]-(5-cicloprop¡lmetox¡-1H-¡ndo 1-2-¡l)-metanona;(82) [5-amine-1- (2-methyl-1H-benzylmidazol-5-yl) -1 H -pyrazol-4-l] - (5-cyclopropylmethox-1H- Ndo 1-2-¡l) -methanone;
(83) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-pirazol-4-¡l]-(2,2-difluoro-5H-[1,3]d¡oxolo[4, 5-f]¡ndol-6-¡l)-metanona;(83) [5-amine-1- (2-methyl-1H-benzimidazol-5-yl) -1 H -pyrazol-4-l] - (2,2-difluoro-5H- [1, 3] d¡oxolo [4,5-f] ndol-6-l) -methanone;
(84) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-pirazol-4-¡l]-[6-(3-cloro-p¡r¡d¡n-2-¡l)-1H-¡n dol-2-¡l]-metanona;(84) [5-am-1-1 (2-methyl-1H-benzimidazol-5-yl) -1 H -pyrazol-4-l] - [6- (3-chloro-p¡r¡ d¡n-2-¡l) -1H-¡n dol-2-¡l] -methanone;
(85) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(5-fluoro-p¡r¡d¡n-2-¡l)-1H-¡n dol-2-¡l]-metanona;(85) [5-am-1-1 (2-methyl-1H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6- (5-fluoro-p¡r¡d ¡N-2-¡l) -1H-¡n dol-2-¡l] -methanone;
(86) [5-am¡no-1-(2-metil-1H-bencimidazol-5-il)-1H-p¡razol-4-il]-[6-(6-morfol¡n-4-¡l-p¡r¡daz¡n-3-¡l)-1H-¡ndol-2-¡l]- metanona;(86) [5-am¡no-1- (2-methyl-1H-benzimidazol-5-yl) -1H-p¡razol-4-yl] - [6- (6-morphol-4-¡ lp¡r¡daz¡n-3-¡l) -1H-¡ndol-2-¡l] - methanone;
(87) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-¡l)-1H-p¡razol-4-il]-(5-cloro-6-c¡cloprop¡lmetox¡-1H-¡ndol-2-¡l)-metanona;(87) [5-am-1-1 (2-methyl-1H-benzimidazol-5-l) -1H-p¡razol-4-yl] - (5-chloro-6-c-cycloprop Lmethox-1H-¡ndol-2-¡l) -methanone;
(88) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-¡l)-1H-p¡razol-4-il]-[6-(2,4-difluoro-fen¡l)-1H-¡nd ol-2-¡l]-metanona;(88) [5-am-1-1 (2-methyl-1H-benzimidazol-5-l) -1 H-p.razole-4-yl] - [6- (2,4-difluoro- fen¡l) -1H-¡nd ol-2-¡l] -methanone;
(89) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-¡l)-1H-p¡razol-4-il]-(6-piridazin-4-¡l-1H-¡ndol-2-¡l) -metanona;(89) [5-am-1-1 (2-methyl-1H-benzimidazol-5-l) -1 H-p.razol-4-yl] - (6-pyridazin-4-l-1) 1H-¡ndol-2-¡l) -methanone;
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(90) [5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(3-fluoro-1H-¡ndol-2-¡l)-metanona;(90) [5-amino-1- (2-methyl-1H-benzyldazol-5-l) -1H-prazol-4-l] - (3-fluoro-1H- Ndol-2-¡l) -methanone;
(91) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[5-(1 -isopropil-piperidin-4-il)-6-trifluorometil- 1 H-indol-2- il]-metanona;(91) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [5- (1-isopropyl-piperidin-4-yl) - 6-trifluoromethyl-1 H-indol-2- yl] -methanone;
(92) 2-[5-am¡no-1-(2-met¡l-1H-bencim¡dazol-5-¡l)-1H-p¡razol-4-carbon¡l]-1H-¡ndol-6-carbon¡tr¡lo;(92) 2- [5-am-no-1- (2-methyl-1H-benzimdadazol-5-l) -1H-p¡razol-4-carbonl] -1H-landol -6-carbon¡tr¡lo;
(93) [5-amino-1 -(2-metil-1 H-benci midazol-5-M)-1 H-pirazol-4-il]-[5-(1,2,3,6-tetrahidro-piridin-4-il)-1 H-i ndol-2-il]- metanona;(93) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-M) -1 H -pyrazol-4-yl] - [5- (1,2,3,6-tetrahydro- pyridin-4-yl) -1 Hi ndol-2-yl] -methanone;
(94) [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-(5-p¡peridin-4-il-1 H-indol-2-M) -metanona;(94) [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - (5-pperidin-4-yl-1 H-indole -2-M) -methanone;
(95) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[5-((R)-3-fluoro-pi rrolidin-1 -il metil)-1 H-indol- 2-il]- metanona;(95) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [5 - ((R) -3-fluoro-pi rrolidin- 1-methyl] -1 H-indole-2-yl] -methanone;
(96) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-(6-fluoro-5-piper¡din-4-il-1 H-in dol-2-il)-metanona;(96) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - (6-fluoro-5-piperine-4-yl- 1 H-in dol-2-yl) -methanone;
(97) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-fluoro-5-(1 -metil-piperidin-4-il)-1 H-indol-2-il]- metanona;(97) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6-fluoro-5- (1-methyl-piperidin-4 -il) -1 H-indol-2-yl] - methanone;
(98) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[5-(1 -isopropil-piperidin-4-il)-1 H-indol-2-il]-metanona;(98) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [5- (1-isopropyl-piperidin-4-yl) - 1 H-indole-2-yl] -methanone;
(99) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-fluoro-5-(1 -isopropil-piperid in-4-il)-1 H-indol- 2-il]- metanona;(99) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6-fluoro-5- (1-isopropyl-piperid in- 4-yl) -1 H-indol-2-yl] -methanone;
(100) [5-am¡no-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-(6-p¡rid¡n-3-il-1 H-indol-2-il)-metanona;(100) [5-am-1-(2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - (6-pridrid-3-yl- 1 H-indole-2-yl) -methanone;
(101) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-¡l]-[5-(6-morfolin-4-¡l-p¡r¡d¡n-3-il)-1 H-indol-2-il]-metanona;(101) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-¡] - [5- (6-morpholin-4-¡lp¡r D¡n-3-yl) -1 H-indol-2-yl] -methanone;
(102) [5-am¡no-1-(2-met¡l-1H-bencim¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(5-p¡r¡d¡n-3-¡l-1H-indol-2-il)-metanona;(102) [5-am-1-1 (2-methyl-1H-benzimdazol-5-l) -1H-p.razole-4-l] - (5-p¡r¡ d¡n-3-¡-1H-indole-2-yl) -methanone;
(103) [5-amino-1 -(2-metil-1 H-bencim¡dazol-5-¡l)-1 H-p¡razol-4-il]-[5-(6-piperazin-1-il-piridin-3-il)-1 H-indol-2-il]- metanona;(103) [5-amino-1 - (2-methyl-1 H-benzimdazol-5-yl) -1 Hp¡razol-4-yl] - [5- (6-piperazin-1-yl- pyridin-3-yl) -1 H-indol-2-yl] -methanone;
(104) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-p¡razol-4-il]-[5-(6-hidroxi-piridin-3-il)-1H-indol-2-il]-metanona;(104) [5-amine-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H-prazol-4-yl] - [5- (6-hydroxy-pyridin-3 -il) -1H-indole-2-yl] -methanone;
(105) [5-am¡no-1-(2-metil-1H-bencimidazol-5-¡l)-1H-p¡razol-4-il]-[6-fluoro-5-(4-metil-piperazin-1-ilmetil)-1 H-indol- 2-il]- metanona;(105) [5-amine-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H-p.razole-4-yl] - [6-fluoro-5- (4-methyl- piperazin-1-ylmethyl) -1 H-indol-2-yl] -methanone;
(106) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(6-fluoro-5-pirrolidin-l-ilmetil-1H-indol-2-¡l)-metanona;(106) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (6-fluoro-5-pyrrolidin-l-ylmethyl-1H-indole- 2-¡) -methanone;
(107) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(1-metil-piperidin-4-il)-1H -indol-2-il]-metanona;(107) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6- (1-methyl-piperidin-4-yl) -1 H - indole-2-yl] -methanone;
(108) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(4-morfolin-4-il-fenil)-1 H-indol-2-il]-metanona;(108) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6- (4-morpholin-4-yl-phenyl) -1 H -indole-2-yl] -methanone;
(109) (5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-(3,4,5,6-tetrahidro-2H-[1,2’] bipiridin-5’-il)-1 H-indol- 2-il]-metanona;(109) (5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6- (3,4,5,6-tetrahydro-2H - [1,2 '] bipyridin-5'-yl) -1 H-indol-2-yl] -methanone;
(110) [5-amino-1-(2-metil-1H-bencimidazol-il)-1H-pirazol-4-il]-[6-(6-piperazin-1-il-piridin-3-il)-1H-indol-2-il]-metanona;(110) [5-amino-1- (2-methyl-1H-benzimidazol-yl) -1 H -pyrazol-4-yl] - [6- (6-piperazin-1-yl-pyridin-3-yl) - 1H-indole-2-yl] -methanone;
(111) [5-amino-1-(2-metil-1H-benc¡midazol-5-il)-1H-pirazol-4-il]-[5-(6-metoxi-piridin-3-il)-1H -indol-2-il]-metanona;(111) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [5- (6-methoxy-pyridin-3-yl) - 1 H -indole-2-yl] -methanone;
(112) [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[5-((S)-3-metil-morfolin-4-il metil)-1 H-indol- 2-il]-(112) [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [5 - ((S) -3-methyl-morpholin-4 -yl methyl) -1 H-indole-2-yl] -
metanona;methanone;
(113) [5-ami no-1-(2-metil-1 H-benci midazol-5-il)-1H-pirazol-4-il]-[6-((R)-3-fluoro-pirrolidin-1-il metil)-1 H-indol- 2-II]- metanona;(113) [5-ami no-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6 - ((R) -3-fluoro-pyrrolidin- 1-yl methyl) -1 H-indole-2-II] - methanone;
(114) [5-ami no-1-(2-met¡l-1 H-benclmldazol-5-il)-1 H-pi razol-4-¡l]-[5-(2,5-d¡met¡l-pirrolidin-1-il metil)-1 H-indol- 2-il]-(114) [5-ami no-1- (2-meti-1 H-benclmldazol-5-yl) -1 H-pi razol-4-¡] - [5- (2,5-d¡ methyl-pyrrolidin-1-yl methyl) -1 H-indol-2-yl] -
metanona;methanone;
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(115) [5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-p¡razol-4-il]-[5-(3-fluoro-piper¡d¡n-1-ilmet¡l)-1H-indol-2-¡l]- metanona;(115) [5-amino-1- (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-yl] - [5- (3-fluoro-piper D¡n-1-ilmet¡l) -1H-indole-2-¡] - methanone;
(116) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pi razol-4-il]-[5-(3,3-difluoro-piperid¡ n-1 -ilmetil)-1 H-¡ndol- 2-¡l]- metanona;(116) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pi razol-4-yl] - [5- (3,3-difluoro-piperid¡ n- 1-methylmethyl) -1 H-α-2-l] - methanone;
(117) [5-amino-1 -(2-metil-1 H-benc¡midazol-5-il)-1 H-pirazol-4-il]-{6-[2-(4-metil-piperazin-1 -il) piridin-4-il]-1 H-indol- 2-il}- metanona;(117) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - {6- [2- (4-methyl-piperazin- 1-yl) pyridin-4-yl] -1 H-indol-2-yl} -methanone;
(118) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-(6-piridin-4-il-1 H-indol-2-il)-metanona;(118) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (6-pyridin-4-yl-1 H-indole-2 -il) -methanone;
(119) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-p¡ razol-4-il]-[5-(4-fl uoropiperidi n-1 -ilmetil )-1 H-i ndol-2-il]-(119) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 Hp¡ razol-4-yl] - [5- (4-fl uoropiperidi n-1-methylmethyl) - 1 Hi ndol-2-il] -
metanona;methanone;
(120) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pi razol-4-il]-[5-(4,4-difluoro-piperid¡ n-1 -ilmetil)-1 H-indol- 2-il]- metanona;(120) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pi razol-4-yl] - [5- (4,4-difluoro-piperid¡ n- 1-methylmethyl) -1 H-indol-2-yl] -methanone;
(121) [5-amino-1-(2-d¡fluoromet¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-[5-(1-met¡l-p¡per¡d¡n-4 -il)-1 H-indol-2-M]- metanona;(121) [5-amino-1- (2-d¡fluoromet¡l-1H-benzmdadazol-5-¡) -1H-p¡razol-4-¡] - [5- (1 -met¡lp¡per¡d¡n-4 -il) -1 H-indole-2-M] - methanone;
(122) [5-amino-1-(2-d¡fluoromet¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(1H-¡ndol-2-¡l)-metanona;(122) [5-amino-1- (2-d¡fluoromet¡l-1H-benz¡m¡dazol-5-¡) -1H-p¡razol-4-¡] - (1H-landol -2-¡) -methanone;
(123) [5-ami no-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[5-(3,3-difluoro-pirrolidin-1 -il metil)-1 H-indol- 2-il]- metanona;(123) [5-ami no-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [5- (3,3-difluoro-pyrrolidin-1 - methyl) -1 H-indole-2-yl] -methanone;
(124) [5-amino-1 -(2-metil-1 H-benc¡ midazol-5-il)-1 H-pirazol-4-il]-[5-(1 -ciclopentil-piperidin-4-il )-1 H-indol-2-il]-(124) [5-amino-1 - (2-methyl-1 H-benzyl midazol-5-yl) -1 H -pyrazol-4-yl] - [5- (1-cyclopentyl-piperidin-4-yl ) -1 H-indole-2-yl] -
metanona;methanone;
(125) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[5-(1-ciclohexil-piperidin-4-il) -1H-indol-2-il]-metanona;(125) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [5- (1-cyclohexyl-piperidin-4-yl) -1H- indole-2-yl] -methanone;
(126) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(4-bromo-1H-pirrol-2-il)-metanona;(126) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (4-bromo-1 H -pyrrol-2-yl) -methanone;
(127) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(1H-pirrol-2-il)-metanona;(127) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (1 H -pyrrol-2-yl) -methanone;
(128) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(4-fenil-1H-pirrol-2-il)-metanona;(128) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (4-phenyl-1 H -pyrrol-2-yl) -methanone;
(129) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[4-(3-cloro-fenil)-1H-pirrol-2-il]-metanona;(129) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [4- (3-chloro-phenyl) -1H-pyrrole-2- il] -methanone;
(130) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[4-(4-fluoro-fenil)-1H-pirrol-2-il]-metanona;(130) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [4- (4-fluoro-phenyl) -1H-pyrrole-2- il] -methanone;
(131) [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[4-(3-fluoro-fenil)-1 H-pirrol-2-il]-metanona;(131) [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [4- (3-fluoro-phenyl) -1 H-pyrrole -2-yl] -methanone;
(132) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(6-morfolin-4-ilmetil-1H-in dol-2-il)-metanona;(132) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (6-morpholin-4-ylmethyl-1H-in dol-2-il ) -methanone;
(133) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[4-(2-morfolin-4-il-etilamin o)-1H-indol-2-il]-metanona;(133) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [4- (2-morpholin-4-yl-ethylamin) -1H -indole-2-yl] -methanone;
(134) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[5-(4-metil-piperazina-1-carbonil)-1 H-indol- 2-il]- metanona;(134) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [5- (4-methyl-piperazine-1-carbonyl) -1 H -indole-2-yl] -methanone;
(135) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(2-morfolin-4-il-etilamin o)-1H-indol-2-il]-metanona;(135) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6- (2-morpholin-4-yl-ethylamin) -1H -indole-2-yl] -methanone;
(136) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[5-(piperazina-1-carbonil)-1H-indol-2-il]-metanona;(136) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [5- (piperazine-1-carbonyl) -1H-indole-2- il] -methanone;
(137) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[4-(2-metoxi-etilamino)-1H-indol-2-il]-metanona;(137) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [4- (2-methoxy-ethylamino) -1H-indole-2- il] -methanone;
(138) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[4-(2-hidroxi-1-hidroximetil -etilamino)- 1 H-indol-2-il]- metanona;(138) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [4- (2-hydroxy-1-hydroxymethyl-ethylamino) - 1 H -indole-2-yl] - methanone;
(139) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[4-(2-piridin-4-il-etilamino)-1H-indol-2-il]-metanona;(139) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [4- (2-pyridin-4-yl-ethylamino) -1H- indole-2-yl] -methanone;
(140) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(2-metoxi-etilamino)-1H-indol-2-il]-metanona;(140) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [6- (2-methoxy-ethylamino) -1H-indole-2- il] -methanone;
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(141) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-(6-morfolin-4-il-1H-¡ndol-2-¡l)-metanona;(141) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-l] - (6-morpholin-4- il-1H-¡ndol-2-¡l) -methanone;
(142) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-(4-morfolin-4-il-1H-¡ndol-2-¡l)-metanona;(142) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-l] - (4-morpholin-4- il-1H-¡ndol-2-¡l) -methanone;
(143) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-(4-morfolin-4-ilmet¡l-1H-¡n dol-2-il)-metanona;(143) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-l] - (4-morpholin-4- ilmet¡l-1H-¡n dol-2-il) -methanone;
(144) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-(5-morfolin-4-ilmet¡l-1H-¡n dol-2-il)-metanona;(144) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-l] - (5-morpholin-4- ilmet¡l-1H-¡n dol-2-il) -methanone;
(145) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-[5-(morfolina-4-carbon¡l)-1H-¡ndol-2-il]-metanona;(145) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-l] - [5- (morpholine-4 -carbon¡l) -1H-¡ndol-2-yl] -methanone;
(146) [5-am¡no-1-(2-¡soprop¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-il]-(1H-indol-2-¡l)-metanona;(146) [5-am-1-1 (2-sopropy-1H-benzyldazol-5-l) -1H-pyrazol-4-yl] - (1H-indole-2- L) -methanone;
(147) [5-am¡no-1-(2-prop¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-(1H-indol-2-¡l)-metanona;(147) [5-amine-1- (2-propyl-1H-benzyldazol-5-l) -1H-pyrazol-4-l] - (1H-indole-2- L) -methanone;
(148) [5-am¡no-1-(1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-il]-(1H-¡ndol-2-il)-metanona;(148) [5-am¡no-1- (1H-benz¡m¡dazol-5-¡) -1H-p¡razol-4-yl] - (1H-¡ndol-2-yl) -methanone ;
(149) [5-am¡no-1-(2-tr¡fluoromet¡l-1H-benc¡m¡dazol-5-il)-1H-p¡razol-4-il]-(1H-¡ndol-2-¡l)-metanona;(149) [5-amine-1- (2-trfluoromethyl-1H-benzyldazol-5-yl) -1 H-prazol-4-yl] - (1 H -indole -2-¡) -methanone;
(150) [5-am¡no-1-(2-et¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(1H-indol-2-¡l)-metanona;(150) [5-am¡no-1- (2-et¡l-1H-benc¡m¡dazol-5-¡l) -1H-p¡razol-4-¡l] - (1H-indole- 2-¡) -methanone;
(151) [5-am¡no-1-(2-benc¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-(1H-indol-2-¡l)metanona;(151) [5-am-1-1 (2-benzyl-1H-benzyldazol-5-l) -1H-pyrazol-4-l] - (1H-indole-2- L) methanone;
(152) 1-(4-{2-[5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-carbon¡l]-1H-¡ndol-5-¡lmet¡l}-piperazin- 1-il)- etanona;(152) 1- (4- {2- [5-amine-1- (2-methyl-1H-benzyldazol-5-l) -1H-pyrazole-4-carbonl) ] -1H-¡ndol-5-¡lmet¡l} -piperazin-1-yl) -ethanone;
(153) [5-am¡no-1-(2-met¡l-1H-bendm¡dazol-5-¡l)-1H-pirazol-4-¡l]-[5-(4-metanosulfon¡l-p¡peraz¡n -1 -ilmetil)- 1H-indol-2- il]-metanona;(153) [5-am-1-1 (2-met-1-1-blessmdazol-5-1) -1 H -pyrazol-4-1] - [5- (4-methanesulfon) Perazine -1-methylmethyl) -1H-indole-2-yl] -methanone;
(154) [5-am¡no-1-(2-met¡l-1H-bendm¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(5-piperaz¡n-1-¡lmet¡l-1H-¡nd ol-2-¡l)-metanona;(154) [5-am¡no-1- (2-met¡l-1H-bendm¡dazol-5-¡l) -1H-p¡razol-4-¡l] - (5-piperaz¡n- 1-¡lmet¡l-1H-¡nd ol-2-¡l) -methanone;
(155) 1-(4-{2-[5-am¡no-1-(2-met¡l-1H-bendm¡dazol-5-il)-1H-p¡razol-4-carbonil]-1H-indol-6-ilmetil}-piperaz¡n- 1-il)- etanona;(155) 1- (4- {2- [5-amine-1- (2-methyl-1H-blessmdazol-5-yl) -1H-prazol-4-carbonyl] -1H -indole-6-ylmethyl} -piperazine-1-yl) -ethanone;
(156) [5-am¡no-1-(2-met¡l-1H-bendm¡dazol-5-il)-1H-p¡razol-4-il]-[6-(4-metil-piperazin-1-ilmetil)-1H-¡ndol-2-¡l]- metanona;(156) [5-am-n-1- (2-methyl-1H-bendmdadazol-5-yl) -1 H-prazol-4-yl] - [6- (4-methyl-piperazin -1-ilmethyl) -1H-¡ndol-2-¡] - methanone;
(157) [5-am¡no-1-(2-met¡l-1H-benc¡midazol-5-il)-1H-p¡razol-4-il]-[5-(4-metil-piperazin-1-ilmetil)-1H-¡ndol-2-¡l]- metanona;(157) [5-amine-1- (2-methyl-1H-benzylmidazol-5-yl) -1 H -pyrazol-4-yl] - [5- (4-methyl-piperazin -1-ilmethyl) -1H-¡ndol-2-¡] - methanone;
(158) [5-am¡no-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-(5-pirrolidin-1-ilmetil-1 H-ind ol-2-il)-metanona;(158) [5-amine-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (5-pyrrolidin-1-ylmethyl-1 H-ind ol-2-yl) -methanone;
(159) [5-am¡no-1-(2-metil-1H-bendmidazol-5-¡l)-1H-p¡razol-4-il]-(4-fluoro-1H-indol-2-¡l)-metanona;(159) [5-am¡no-1- (2-methyl-1H-bendmidazol-5-¡) -1H-p¡razol-4-yl] - (4-fluoro-1H-indole-2-¡ l) -methanone;
(160) [5-am¡no-1-(2-met¡l-1H-bendm¡dazol-5-il)-1H-p¡razol-4-il]-(5-fluoro-1H-¡ndol-2-¡l)-metanona;(160) [5-am-1-1 (2-methyl-1H-blessmdazol-5-yl) -1 H-p.razole-4-yl] - (5-fluoro-1 H -indole -2-¡) -methanone;
(161) [5-am¡no-1-(2-met¡l-1H-bendmidazol-5-il)-1H-p¡razol-4-il]-(6-fluoro-1H-¡ndol-2-¡l)-metanona;(161) [5-am-1-1 (2-methyl-1H-bendmidazol-5-yl) -1 H-p.razole-4-yl] - (6-fluoro-1 H-landol-2 -L) -methanone;
(162) [5-am¡no-1-(2-met¡l-1H-bendm¡dazol-5-¡l)-1H-p¡razol-4-il]-(1H-p¡rrolo[2,3-b]p¡r¡d¡n-2-¡l)-metanona;(162) [5-am-1-1 (2-met-1-1-blessmdazol-5-1) -1 H-p.razole-4-yl] - (1 H-p.rrolo [2 , 3-b] p¡r¡d¡n-2-¡) -methanone;
(163) [5-am¡no-1-(2-met¡l-1H-bendmidazol-5-il)-1H-p¡razol-4-il]-(5-fluoro-6-morfol¡n-4-¡lmet¡l-1H-¡ndol-2-il)-metanona;(163) [5-am-n-1- (2-methyl-1 H-bendmidazol-5-yl) -1 H-prazol-4-yl] - (5-fluoro-6-morphol- 4-¡lmet¡l-1H-¡ndol-2-yl) -methanone;
(164) ácido 2-[5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-carbonil]-1H-indol-5-carboxílico;(164) 2- [5-Amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-carbonyl] -1 H -indole-5-carboxylic acid;
(165) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5-metoxi-1H-indol-2-il)-metanona;(165) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (5-methoxy-1H-indole-2-yl) -methanone;
(166) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(4,6-dimetoxi-1H-indol-2-il)-metanona;(166) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (4,6-dimethoxy-1H-indole-2-yl) -methanone ;
(167) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(4-metoxi-1H-indol-2-il)-metanona;(167) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (4-methoxy-1H-indole-2-yl) -methanone;
(168) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(6-metoxi-1H-indol-2-il)-metanona;(168) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (6-methoxy-1H-indole-2-yl) -methanone;
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(169) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-(4,6-d¡met¡l-1H-¡ndol-2-¡l)-metanona;(169) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-l] - (4,6-d) met¡l-1H-¡ndol-2-¡l) -methanone;
(170) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-(5-ferf-but¡l-1H-¡ndol-2-¡l)-metanona;(170) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-l] - (5-ferf-but) l-1H-¡ndol-2-¡l) -methanone;
(171) [5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(5-¡soprop¡l-1H-¡ndol-2-¡l)-metanona;(171) [5-amino-1- (2-methyl-1H-benzyldazol-5-l) -1H-prazol-4-l] - (5-sopropyl) -1H-¡ndol-2-¡l) -methanone;
(172) [5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-p¡razol-4-¡l]-(5-benciloxi-1H-indol-2-¡l)-metanona;(172) [5-amino-1- (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-l] - (5-benzyloxy-1 H-indole -2-¡) -methanone;
(173) [5-amino-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-il]-(4-benciloxi-1H-indol-2-¡l)-metanona;(173) [5-amino-1- (2-methyl-1H-benzimdazol-5-yl) -1H-pyrazol-4-yl] - (4-benzyloxy-1H-indole-2-¡ l) -methanone;
(174) [5-amino-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-il]-(5,6-dimetoxi-1H-indol-2-¡l)-metanona;(174) [5-amino-1- (2-methyl-1H-benzimdazol-5-l) -1H-pyrazol-4-yl] - (5,6-dimethoxy-1H-indole-2 -L) -methanone;
(175) [5-amino-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-il]-(6-ferf-butil-1H-indol-2-¡l)-metanona;(175) [5-amino-1- (2-methyl-1H-benzamdazol-5-yl) -1H-pyrazol-4-yl] - (6-ferf-butyl-1H-indole-2 -L) -methanone;
(176) [5-amino-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-il]-(5-fluoro-4-trifluorometil-1H-indol-2-il)-metanona;(176) [5-amino-1- (2-methyl-1H-benzimdazol-5-l) -1H-pyrazol-4-yl] - (5-fluoro-4-trifluoromethyl-1H-indole -2-yl) -methanone;
(177) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-(5-fenox¡-1H-¡ndol-2-¡l)-metanona;(177) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1H-pyrazol-4-l] - (5-phenoxy-1H -¡Ndol-2-¡l) -methanone;
(178) [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-(6-metilsulfanil-1 H-indol-2-M )-metanona;(178) [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (6-methylsulfanyl-1 H-indole-2-M) - methanone;
(179) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(4-ferf-butil-1H-¡ndol-2-¡l)-metanona;(179) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1H-p.razole-4-l] - (4-ferf- butyl-1H-landol-2-l) -methanone;
(180) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-il]-(5-met¡l-1H-¡ndol-2-¡l)-metanona;(180) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1H-prazol-4-yl] - (5-methyl) -1H-¡ndol-2-¡l) -methanone;
(181) [5-amino-1 -(2-met¡l-1 H-benc¡m¡dazol-5-¡l)-1 H-p¡razol-4-il]-(5-etil-1 H-indol-2-il)-metanona;(181) [5-Amino-1 - (2-methyl-1 H-benzyldazol-5-l) -1 Hp.razol-4-yl] - (5-ethyl-1 H- indole-2-yl) -methanone;
(182) [5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(5-fluoro-6-tr¡fluoromet¡l-1H-¡ndol-2-¡l)-metanona;(182) [5-amino-1- (2-methyl-1H-benzyldazol-5-l) -1H-prazol-4-l] - (5-fluoro-6- trfluorometl-1H-¡ndol-2-¡l) -methanone;
(183) [5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(6-fluoro-5-metox¡-1H-¡ndol-2 -il)-metanona;(183) [5-amino-1- (2-methyl-1H-benzyldazol-5-l) -1H-prazol-4-l] - (6-fluoro-5- methox¡-1H-¡ndol-2-yl) -methanone;
(184) [5-amino-1-(2-met¡l-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(6-cloro-5-metoxi-1H-indol-2-il)-metanona;(184) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (6-chloro-5-methoxy-1H-indole-2- il) -methanone;
(185) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5-cloro-6-metoxi-1H-indol-2-il)-metanona;(185) [5-amine-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (5-chloro-6-methoxy-1H-indole- 2-yl) -methanone;
(186) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(6-isopropoxi-1H-indol-2-il)-metanona;(186) [5-amine-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (6-isopropoxy-1H-indole-2-yl) -metanone;
(187) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(6-benciloxi-1H-indol-2-il)-metanona;(187) [5-amine-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (6-benzyloxy-1H-indole-2-yl) -metanone;
(188) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(4-isopropoxi-1H-indol-2-il)-metanona;(188) [5-amine-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (4-isopropoxy-1H-indole-2-yl) -metanone;
(189) [5-am¡no-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(2,3-dihidro-6H-[1,4]dioxino[2, 3-f]indol-7-¡l)- metanona;(189) [5-amine-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (2,3-dihydro-6 H- [1,4] dioxin [2, 3-f] indole-7-l) - methanone;
(190) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(4,6-di-ferf-butil-1H-indol-2-il) -metanona;(190) [5-amine-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (4,6-di-ferf-butyl-1 H- indole-2-yl) -methanone;
(191) 2-[5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-pirazol-4-carbon¡l]-1H-indol-4-carbonitrilo;(191) 2- [5-amine-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-carbonyl] -1H-indole-4-carbonitrile;
(192) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5-imidazol-1-il-1H-indol-2-il) -metanona;(192) [5-amine-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (5-imidazol-1-yl-1H-indole- 2-yl) -methanone;
(193) [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5-trifluorometilsulfanil-1H-indol-2-il)-metanona;(193) [5-amine-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (5-trifluoromethylsulfanyl-1 H -indole-2-yl) -metanone;
(194) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5-met¡lsulfan¡l-1H-indol-2-il)-metanona;(194) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (5-methylsulfan¡l-1 H -indole-2-yl) -metanone;
(195) [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(5-metanosulfon¡l-1H-indol-2-il)-metanona;(195) [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H-p.razol-4-l] - (5-methanesulfon) l-1H-indole-2-yl) -methanone;
(196) [5-amino-1 -(2-metil-1 H-benci midazol-5-il)-1 H-pirazol-4-il]-[6-(4,4-difl uoro-piperidi n-1 -ilmetil)-1 H-indol- 2-il]-(196) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6- (4,4-difl uoro-piperidi n- 1-methylmethyl) -1 H-indole-2-yl] -
metanona;methanone;
(197) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-(4-fluoro-pi peridin-1 -ilmetil)-1 H-indol-2-il]- metanona;(197) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6- (4-fluoro-pi peridin-1-methylmethyl) -1 H-indole-2-yl] - methanone;
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(198) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(oxetan-3-iloxi)-1H-indol-2-il]-metanona;(198) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [6- (oxetan-3-yloxy) -1H-indole-2- il] -methanone;
(199) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(6-hidroxi-1H-indol-2-il)-metanona;(199) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (6-hydroxy-1H-indole-2-yl) -methanone;
(200) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(6-metanosulfonilo-1H-indol-2-il)-metanona;(200) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (6-methanesulfonyl-1 H -indole-2-yl) -methanone;
(201) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(4,5-dibromo-1H-pirrol-2-il)-metanona;(201) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (4,5-dibromo-1H-pyrrol-2-yl) -methanone ;
(202) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(4,5-difenil-1H-pirrol-2-il)-metanona; y(202) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (4,5-diphenyl-1 H -pyrrol-2-yl) -methanone ; Y
(203) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(4,5-dipiridin-3-il-1H-pirrol-2-il)-metanona.(203) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (4,5-dipyridin-3-yl-1H-pyrrole-2- il) -methanone.
(204) [5-amino-1-(2-metil-3H-bencimidazol-5-il)-1H-pirazol-4-il]-(6-cloro-1H-indol-2-il)-metanona;(204) [5-amino-1- (2-methyl-3H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (6-chloro-1H-indole-2-yl) -methanone;
(205) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5-cloro-1H-indol-2-il)-metanona;(205) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (5-chloro-1H-indole-2-yl) -methanone;
(206) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(1H-indol-3-il)-metanona;(206) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (1H-indole-3-yl) -methanone;
(207) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(1H-indol-6-il)-metanona;(207) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (1H-indole-6-yl) -methanone;
(208) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5-bromo-6-fluoro-1H-indol-2-il)-metanona;(208) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (5-bromo-6-fluoro-1H-indole-2-yl) -metanone;
(209) [5-amino-1-(2-etil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5-bromo-6-fluoro-1H-indol-2-il) -metanona;(209) [5-amino-1- (2-ethyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (5-bromo-6-fluoro-1 H -indole-2-yl) -metanone;
(210) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5-trifluorometil-1H-indol-2-il)-metanona;(210) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (5-trifluoromethyl-1 H -indole-2-yl) -methanone;
(211) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5-trifluorometoxi-1H-indol-2-il)-metanona;(211) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (5-trifluoromethoxy-1 H-indol-2-yl) -methanone;
(212) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(4,6-dicloro-1H-indol-2-il)-metanona;(212) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (4,6-dichloro-1H-indole-2-yl) -methanone ;
(213) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(6-bromo-4-fluoro-1H-indol-2-il)-metanona;(213) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (6-bromo-4-fluoro-1H-indole-2-yl) -metanone;
(214) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(6-trifluorometoxi-1H-indol-2-il)-metanona;(214) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (6-trifluoromethoxy-1 H -indole-2-yl) -methanone;
(215) [5-amino-1-(2-etil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5-trifluorometoxi-1H-indol-2-il )-metanona;(215) [5-amino-1- (2-ethyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (5-trifluoromethoxy-1 H -indole-2-yl) -methanone;
(216) [5-amino-1-(2-etil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5-trifluorometil-1H-indol-2-il)-metanona;(216) [5-amino-1- (2-ethyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (5-trifluoromethyl-1 H -indole-2-yl) -methanone;
(217) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5,6-dicloro-1H-indol-2-il)-metanona;(217) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (5,6-dichloro-1H-indole-2-yl) -methanone ;
(218) [5-amino-1-(2-etil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(6-bromo-5-fluoro-1H-indol-2-il) -metanona;(218) [5-amino-1- (2-ethyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (6-bromo-5-fluoro-1H-indole-2-yl) -metanone;
(219) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(4,5-dicloro-1H-indol-2-il)-metanona;(219) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (4,5-dichloro-1H-indole-2-yl) -methanone ;
(220) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(4,6-difluoro-1H-indol-2-il)-metanona;(220) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (4,6-difluoro-1H-indole-2-yl) -methanone ;
(221) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(3-cloro-piridin-4-il)-1H-in dol-2-il]-metanona;(221) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6- (3-chloro-pyridin-4-yl) -1 H- in dol-2-il] -methanone;
(222) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(6-metil-piridina-3-il)-1H-indol-2-il]-metanona;(222) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6- (6-methyl-pyridine-3-yl) -1 H- indole-2-yl] -methanone;
(223) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-(5-fluoro-piridin-3-il)-1 H-in dol-2-il]-metanona;(223) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6- (5-fluoro-pyridin-3-yl) - 1 H-in dol-2-yl] -methanone;
(224) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(2-trifluorometil-piridin-3-il)-1H-indol-2-il]-metanona;(224) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6- (2-trifluoromethyl-pyridin-3-yl) -1 H- indole-2-yl] -methanone;
(225) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(5-cloro-2-metoxi-piridin-3-il)-1H-indol- 2-il]- metanona;(225) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [6- (5-chloro-2-methoxy-pyridin-3-yl ) -1H-indole-2-yl] -methanone;
(226) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(5-cloro-piridin-3-il)-1H-in dol-2-il]-metanona;(226) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6- (5-chloro-pyridin-3-yl) -1 H- in dol-2-il] -methanone;
(227) [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-(6-tiofen-3-il-1 H-indol-2-il) -metanona;(227) [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - (6-thiophen-3-yl-1 H-indole-2 -il) -methanone;
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(228) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(4-cloropiridin-3-il)-1H-in dol-2-il]-metanona;(228) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [6- (4-chloropyridin-3-yl) -1H-in dol -2-yl] -methanone;
(229) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-(6-tiofen-2-il-1 H-indol-2-il) -metanona;(229) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (6-thiophen-2-yl-1 H-indole-2 -il) -methanone;
(230) [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[6-(3-fluoro-piridin-4-il)-1 H-in dol-2-il]-metanona;(230) [5-amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6- (3-fluoro-pyridin-4-yl) - 1 H-in dol-2-yl] -methanone;
(231) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(2-trifluorometil-piridin-4-il)-1H-indol-2-il]-metanona;(231) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [6- (2-trifluoromethyl-pyridin-4-yl) -1H- indole-2-yl] -methanone;
(232) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[5-(3,3-difluoro-pirrolidina-1carbonil)-1H-indol- 2-il]- metanona;(232) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [5- (3,3-difluoro-pyrrolidine-1carbonyl) -1H- indole-2-yl] -methanone;
(233) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[5-(2,6-dimetil-morfolina-4-carbonil)-1H-indol- 2-il]- metanona;(233) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [5- (2,6-dimethyl-morpholine-4-carbonyl) - 1H-indole-2-yl] -methanone;
(234) [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[5-([1,4'] bipiperidinil-1 '-carbonil)-1 H-indol-2-il]- metanona;(234) [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [5 - ([1,4 '] bipiperidinyl-1' - carbonyl) -1 H-indol-2-yl] -methanone;
(235) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-5-[4-(2,2,2-trifluoro-etil)-piperazina-1-carbonil]- 1H- indol-2-il}-metanona;(235) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] -5- [4- (2,2,2-trifluoro-ethyl) - piperazine-1-carbonyl] -1H-indol-2-yl} -methanone;
(236) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-{5-[4-(2-hidroxi-etil)-piperazina-1-carbonil]- 1 H-indol- 2-il}-metanona;(236) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - {5- [4- (2-hydroxy-ethyl) -piperazine-1 -carbonyl] -1 H-indol-2-yl} -methanone;
(237) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[5-(3,3,4,4-tetrafluoro-pirrolidina-1-carbonil)- 1 H-indol- 2-il]-metanona;(237) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [5- (3,3,4,4-tetrafluoro-pyrrolidine-1 -carbonyl) -1 H-indole-2-yl] -methanone;
(238) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[5-((R)-3-fluoro-pirrolidina-1-carbonil)-1H-indol- 2-il]- metanona;(238) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [5 - ((R) -3-fluoro-pyrrolidine-1-carbonyl ) -1H-indole-2-yl] -methanone;
(239) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[5-((S)-3-fluroro-pirrolidina-1-carbonil)-1H-indol- 2-il]- metanona;(239) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [5 - ((S) -3-fluroro-pyrrolidine-1-carbonyl ) -1H-indole-2-yl] -methanone;
(240) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[4-(4-metoxi-fenil)-1H-pirrol-2-il]-metanona;(240) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [4- (4-methoxy-phenyl) -1H-pyrrole-2- il] -methanone;
(241) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[4-(3-metoxi-fenil)-1H-pirrol-2-il]-metanona;(241) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [4- (3-methoxy-phenyl) -1H-pyrrole-2- il] -methanone;
(242) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[4,5-bis-(3-fluoro-fenil)-1H-pirrol-2-il]-metanona;(242) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [4,5-bis- (3-fluoro-phenyl) -1 H- pyrrol-2-yl] -methanone;
(243) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[4,5-bis-(4-metoxi-fenil)-1H -pirrol-2-il]-metanona;(243) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [4,5-bis- (4-methoxy-phenyl) -1 H - pyrrol-2-yl] -methanone;
(244) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[4-(2,4-difluoro-fenil)-1H-pirrol-2-il]-metanona;(244) [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [4- (2,4-difluoro-phenyl) -1H-pyrrole- 2-yl] -methanone;
(245) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[4-(4-trifluorometoxi-fenil)-1H-pirrol-2-il]-metanona;(245) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [4- (4-trifluoromethoxy-phenyl) -1H-pyrrole-2- il] -methanone;
(246) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[4,5-bis-(3-metoxi-fenil)-1H -pirrol-2-il]-metanona;(246) [5-Amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [4,5-bis- (3-methoxy-phenyl) -1 H - pyrrol-2-yl] -methanone;
(247) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-benzofurano-2-il-metanona;(247) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] -benzofuran-2-yl-methanone;
(248) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-benzo[b] tiofen-2-il-metanona;(248) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] -benzo [b] thiophene-2-yl-methanone;
(249) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-benzotiazol-2-il-metanona;(249) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] -benzothiazol-2-yl-methanone;
(250) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(4-fluoro-fenil)-metanona;(250) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (4-fluoro-phenyl) -methanone;
(251) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(3-cloro-fenil)-metanona;(251) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (3-chloro-phenyl) -methanone;
(252) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-quinolin-3-il-metanona;(252) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] -quinolin-3-yl-methanone;
(253) [5-amino-1-(2-metil-+1H-bencimidazol-5-il)-1H-pirazol-4-il]-quinolin-7-il-metanona; y(253) [5-amino-1- (2-methyl- + 1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] -quinolin-7-yl-methanone; Y
(254) [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-quinolin-6-il-metanona.(254) [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] -quinolin-6-yl-methanone.
Los anteriores compuestos representados por formula (I) de la presente Invención y descripción y las sales farmacéuticamente aceptables de los mismos son útiles como compuestos que tienen una actividad de inhibición de las quinasas de la familia del receptor del factor de crecimiento de fibroblastos (FGFR). Por lo tanto, los compuestos son útiles en la prevención y/o el tratamiento del cáncer (por ejemplo, cáncer de mama, leucemia mielocítica aguda, 5 cáncer de páncreas, cáncer de vejiga, cáncer de próstata, cáncer de esófago, angiogénesis, cáncer de estómago, cáncer de cuerpo uterino, cáncer de ovario, tumor cerebral (incluyendo glioblastoma), cáncer de colon, mieloma múltiple, hepatocarcinoma, cáncer pulmonar (incluyendo cánceres de pulmón de células pequeñas y de células no- pequeñas), y cáncer de tiroides.The above compounds represented by formula (I) of the present invention and description and the pharmaceutically acceptable salts thereof are useful as compounds having an inhibition activity of the kinases of the fibroblast growth factor receptor family (FGFR) . Therefore, the compounds are useful in the prevention and / or treatment of cancer (eg, breast cancer, acute myelocytic leukemia, 5 pancreatic cancer, bladder cancer, prostate cancer, esophageal cancer, angiogenesis, cancer Stomach, uterine body cancer, ovarian cancer, brain tumor (including glioblastoma), colon cancer, multiple myeloma, hepatocarcinoma, lung cancer (including small cell and non-small cell lung cancers), and thyroid cancer .
Los compuestos de la presente invención y descripción y las sales de los mismos se pueden formular en 10 comprimidos, polvos, gránulos finos, gránulos, comprimidos recubiertos, cápsulas, jarabes, trociscos, inhalantes, supositorios, inyecciones, ungüentos, ungüentos para los ojos, gotas para los ojos, gotas nasales, gotas para los oídos, cataplasmas, lociones, y similares por métodos convencionales. Para la formulación, excipientes convencionales, se pueden utilizar aglutinantes, lubricantes, colorantes, agentes aromatizantes, y si es necesario, estabilizantes, emulsionantes, absorbefacientes, surfactantes, agentes de ajuste de pH, conservantes, antioxidantes, 15 y similares. Los compuestos de la presente invención o descripción se formulan, mediante la combinación de ingredientes que se utilizan generalmente como materiales para preparaciones farmacéuticas, utilizando métodos convencionales.The compounds of the present invention and description and salts thereof can be formulated into 10 tablets, powders, fine granules, granules, coated tablets, capsules, syrups, troches, inhalants, suppositories, injections, ointments, eye ointments, eye drops, nasal drops, ear drops, poultices, lotions, and the like by conventional methods. For the formulation, conventional excipients, binders, lubricants, colorants, flavoring agents, and if necessary, stabilizers, emulsifiers, absorbents, surfactants, pH adjusting agents, preservatives, antioxidants, 15 and the like can be used. The compounds of the present invention or description are formulated, by combining ingredients that are generally used as materials for pharmaceutical preparations, using conventional methods.
Por ejemplo, para producir formulaciones orales, los compuestos de la presente invención o descripción o sales farmacéuticamente aceptables de los mismos, se combinan con excipientes, y si es necesario, aglutinantes, agentes 20 de desintegración, lubricantes, colorantes, agentes aromatizantes, y similares; y luego se formulan en polvos, gránulos finos, gránulos, comprimidos, comprimidos recubiertos, cápsulas, y similares por métodos convencionales.For example, to produce oral formulations, the compounds of the present invention or description or pharmaceutically acceptable salts thereof, are combined with excipients, and if necessary, binders, disintegrating agents, lubricants, colorants, flavoring agents, and the like. ; and then formulated in powders, fine granules, granules, tablets, coated tablets, capsules, and the like by conventional methods.
Los ingredientes incluyen, por ejemplo, aceites animales y vegetales tales como aceites de soja, sebo de buey y glicéridos sintéticos; hidrocarburos tales como parafina líquida, escualeno y parafina sólida; aceites de ésteres tales como miristato de octildodecilo y miristato de isopropilo; alcoholes superiores tales como alcohol cetoestearílico y 25 alcohol behenílico; resinas de silicona; aceites de silicona; surfactantes tales como ésteres de ácidos grasos de polioxietileno, ésteres de ácidos grasos de sorbitán, ésteres de ácidos grasos de glicerina, ésteres de ácidos grasos de sorbitán de polioxietileno, aceites de ricino de polioxietileno hidrogenado, y copolímeros de bloque de polioxietileno/polioxipropileno; polímeros solubles en agua tales como hidroxietil celulosa, ácidos poliacrílicos, polímeros de carboxivinilo, polietilenglicol, polivinilpirrolidona, y celulosa de metilo; alcoholes inferiores tales como 30 etanol e isopropanol; polialcoholes tales como glicerina, propilenglicol, dipropilenglicol y sorbitol; sacáridos tales como glucosa y sacarosa; polvos inorgánicos tales como anhídrido silícico, silicato de magnesio y aluminio, y silicato de aluminio; y agua purificada.The ingredients include, for example, animal and vegetable oils such as soybean oils, beef tallow and synthetic glycerides; hydrocarbons such as liquid paraffin, squalene and solid paraffin; ester oils such as octyldodecyl myristate and isopropyl myristate; higher alcohols such as ketostearyl alcohol and behenyl alcohol; silicone resins; silicone oils; surfactants such as polyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, hydrogenated polyoxyethylene / polyoxyethylene castor oils, and polyoxyethylene / polyoxypropylene block copolymers; water soluble polymers such as hydroxyethyl cellulose, polyacrylic acids, carboxyvinyl polymers, polyethylene glycol, polyvinyl pyrrolidone, and methyl cellulose; lower alcohols such as ethanol and isopropanol; polyalcohols such as glycerin, propylene glycol, dipropylene glycol and sorbitol; saccharides such as glucose and sucrose; inorganic powders such as silicic anhydride, magnesium aluminum silicate, and aluminum silicate; and purified water.
Los excipientes incluyen, por ejemplo, lactosa, almidón de maíz, sacarosa, glucosa, manitol, sorbitol, celulosa cristalina y dióxido de silicio.Excipients include, for example, lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose and silicon dioxide.
35 Los aglutinantes incluyen, por ejemplo, alcohol polivinílico, éter polivinílico, metilcelulosa, etilcelulosa, goma arábiga, tragacanto, gelatina, goma laca, hidroxipropil metil celulosa, hidroxipropil celulosa, polivinilpirrolidona, polímero de bloque de polipropilenglicol/polioxietileno y meglumina.The binders include, for example, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polypropylene glycol / polyoxyethylene block polymer.
Los agentes disgregantes incluyen, por ejemplo, almidón, agar, polvo de gelatina, celulosa cristalina, carbonato de calcio, bicarbonato de sodio, citrato de calcio, dextrano, pectina y carboximetilcelulosa de calcio.Disintegrating agents include, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextran, pectin and calcium carboxymethylcellulose.
40 Los lubricantes incluyen, por ejemplo, estearato de magnesio, talco, polietilenglicol, sílica y aceite vegetal endurecido.40 Lubricants include, for example, magnesium stearate, talc, polyethylene glycol, silica and hardened vegetable oil.
Se utilizan los colorantes autorizados para uso como aditivos para productos farmacéuticos. Los agentes aromatizantes utilizados incluyen, por ejemplo, polvo de cacao, mentol, polvo aromático, aceite de menta, borneol y canela en polvo.The dyes authorized for use as additives for pharmaceutical products are used. The flavoring agents used include, for example, cocoa powder, menthol, aromatic powder, peppermint oil, borneol and cinnamon powder.
45 Por supuesto, estos comprimidos y gránulos se pueden recubrir con azúcar, o si es necesario, otros recubrimientos apropiados. Alternativamente, cuando se producen preparaciones líquidas tales como jarabes e inyecciones, los compuestos de la presente invención o descripción o las sales farmacéuticamente aceptables de los mismos se combinan con agentes de ajuste de pH, solubilizantes, agentes isotonizantes, o semejantes, y si es necesario, agentes solubilizantes, estabilizantes, y semejantes, y luego formulados utilizando métodos convencionales.Of course, these tablets and granules can be coated with sugar, or if necessary, other suitable coatings. Alternatively, when liquid preparations such as syrups and injections are produced, the compounds of the present invention or description or the pharmaceutically acceptable salts thereof are combined with pH adjusting agents, solubilizers, isotonizing agents, or the like, and if necessary , solubilizing agents, stabilizers, and the like, and then formulated using conventional methods.
50 Los métodos para producir preparaciones externas no están limitados, y pueden ser producidos por métodos convencionales. Diversos materiales convencionales para productos farmacéuticos, cuasi-fármacos, cosméticos, y similares se pueden utilizar como materiales de base en la producción. Específicamente, los materiales de base utilizados incluyen, por ejemplo, aceites animales y vegetales, aceites minerales, aceites de éster, ceras, alcoholes superiores, ácidos grasos, aceites de silicona, surfactantes, fosfolípidos, alcoholes, polialcoholes, polímeros solubles50 The methods for producing external preparations are not limited, and can be produced by conventional methods. Various conventional materials for pharmaceuticals, quasi-drugs, cosmetics, and the like can be used as base materials in production. Specifically, the base materials used include, for example, animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, polyalcohols, soluble polymers
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en agua, minerales de arcilla y agua purificada. Adlclonalmente, como es necesario, es posible adicionar agentes de ajuste del pH, antloxldantes, agentes quelantes, conservantes, colorantes, agentes aromatizantes, y semejantes. Sin embargo, los materiales de base para las preparaciones externas de la presente Invención o descripción no se limitan a los mismos.in water, clay minerals and purified water. Adlclonally, as necessary, it is possible to add pH adjusting agents, antloxldants, chelating agents, preservatives, colorants, flavoring agents, and the like. However, the base materials for the external preparations of the present invention or description are not limited thereto.
Adlclonalmente, si es necesario, las preparaciones se pueden combinar con componentes que tienen una actividad de Inducir la diferenciación, o componentes tales como agentes potenciadores de flujo sanguíneo, agentes antlmlcroblanos, agentes antiinflamatorios, agentes activadores de células, vitaminas, aminoácidos, humectantes, y agentes queratolítlcos. Los materiales de base descritos anteriormente se pueden adicionar en una cantidad que proporciona una concentración seleccionada por lo general en la producción de preparaciones externas.Adlclonally, if necessary, the preparations can be combined with components that have an activity of Inducing differentiation, or components such as blood flow enhancing agents, anti-lymphoblast agents, anti-inflammatory agents, cell activating agents, vitamins, amino acids, humectants, and keratolytic agents. The base materials described above can be added in an amount that provides a concentration generally selected in the production of external preparations.
Cuando los compuestos de la presente invención o descripción, sales, o hidratos de los mismos se administran, sus formas de dosificación no están particularmente limitados, y se pueden administrar por vía oral o parenteral por métodos utilizados convencionalmente. Se pueden formular y administrar en forma de comprimidos, polvos, gránulos, cápsulas, jarabes, trociscos, inhalantes, supositorios, Inyecciones, ungüentos, ungüentos para los ojos, gotas para los ojos, gotas nasales, gotas para los oídos, cataplasmas, lociones, y similares.When the compounds of the present invention or description, salts, or hydrates thereof are administered, their dosage forms are not particularly limited, and can be administered orally or parenterally by conventionally used methods. They can be formulated and administered in the form of tablets, powders, granules, capsules, syrups, troches, inhalants, suppositories, injections, ointments, eye ointments, eye drops, nasal drops, ear drops, poultices, lotions, and the like
La dosificación de los productos farmacéuticos de la presente invención y descripción se puede seleccionar apropiadamente dependiendo de la severidad de los síntomas, edad, sexo, peso, método de administración, tipo de sal, tipo específico de enfermedad, y semejantes.The dosage of the pharmaceutical products of the present invention and description can be appropriately selected depending on the severity of the symptoms, age, sex, weight, method of administration, type of salt, specific type of disease, and the like.
La dosis varía considerablemente dependiendo del tipo de enfermedad, la gravedad de los síntomas, la edad, el sexo, la sensibilidad al agente, y semejantes del paciente. Por lo general, el agente se administra a un adulto una vez o varias veces al día en una dosis diaria de aproximadamente 0.03 a 1000 mg, preferiblemente 0.1 a 500 mg, y más preferiblemente 0.1 a 100 mg. Cuando se utiliza una inyección, por lo general la dosis diaria es aproximadamente 1 a 3000 mg/kg, preferiblemente aproximadamente 3 a 1000 mg/kg.The dose varies considerably depending on the type of disease, the severity of symptoms, age, sex, sensitivity to the agent, and the like of the patient. Typically, the agent is administered to an adult once or several times a day at a daily dose of about 0.03 to 1000 mg, preferably 0.1 to 500 mg, and more preferably 0.1 to 100 mg. When an injection is used, usually the daily dose is about 1 to 3000 mg / kg, preferably about 3 to 1000 mg / kg.
Cuando se producen los compuestos de la presente invención o descripción, los compuestos de materiales y diversos reactivos pueden formar sales, hidratos, o solvatos. El tipo varía dependiendo del material inicial, solvente utilizado, y semejantes, y no está particularmente limitado siempre que las reacciones no sean inhibidas.When the compounds of the present invention or description are produced, the compounds of materials and various reagents can form salts, hydrates, or solvates. The type varies depending on the initial material, solvent used, and the like, and is not particularly limited as long as the reactions are not inhibited.
Los solventes que se van a utilizar varían dependiendo del material incial, reactivo, y semejantes, y como una cuestión por supuesto, no están particularmente limitados siempre y cuando puedan disolver los materiales iniciales hasta cierto punto sin Inhibir las reacciones.The solvents to be used vary depending on the initial material, reagent, and the like, and as a matter of course, they are not particularly limited as long as they can dissolve the starting materials to some extent without inhibiting the reactions.
Varios Isómeros (por ejemplo, isómeros geométricos, isómeros ópticos basados en carbonos asimétricos, isómeros rotacionales, estereoisómeros y tautómeros) pueden ser purificados y aislados por métodos convencionales de separación tales como recristalización, métodos de sal de diastereómeros, métodos de resolución basados en enzimas, varios métodos cromatográficos (por ejemplo, cromatografía en capa fina, cromatografía de columna, cromatografía líquida de alta resolución y cromatografía de gases).Several Isomers (for example, geometric isomers, optical isomers based on asymmetric carbons, rotational isomers, stereoisomers and tautomers) can be purified and isolated by conventional separation methods such as recrystallization, diastereomer salt methods, enzyme-based resolution methods, various chromatographic methods (for example, thin layer chromatography, column chromatography, high performance liquid chromatography and gas chromatography).
Cuando se obtiene un compuesto de la presente invención o descripción en una forma libre, se puede convertir por métodos convencionales en una sal o hidrato del mismo, que se puede formar a partir del compuesto de la presente invención o descripción. Cuando se obtiene un compuesto de la presente invención o descripción como una sal o hidrato del mismo, se puede convertir por métodos convencionales en una forma libre del compuesto de la presente invención o descripción.When a compound of the present invention or description is obtained in a free form, it can be converted by conventional methods into a salt or hydrate thereof, which can be formed from the compound of the present invention or description. When a compound of the present invention or description is obtained as a salt or hydrate thereof, it can be converted by conventional methods into a free form of the compound of the present invention or description.
Los compuestos de la presente invención y la invención se pueden purificar y aislar utilizando métodos químicos convencionales tales como extracción, concentración, separación por destilación, cristalización, filtración, recristalización, y diversos métodos cromatográficos.The compounds of the present invention and the invention can be purified and isolated using conventional chemical methods such as extraction, concentration, distillation separation, crystallization, filtration, recrystallization, and various chromatographic methods.
Los métodos generales para producir los compuestos de la presente invención y la descripción y ejemplos de trabajo se describen a continuación.The general methods for producing the compounds of the present invention and the description and working examples are described below.
Los compuestos de la presente invención y la descripción se pueden sintetizar mediante diversos métodos. Algunos de ellos se ilustran con referencia a los esquemas mostrados a continuación. Los esquemas son para fines ilustrativos, y la presente invención y la descripción no se limitan a las reacciones químicas y condiciones que se muestran en los mismos. En los esquemas mostrados a continuación, algunos sustituyentes pueden ser omitidos para mayor claridad, pero esto no pretende limitar la descripción de los esquemas. Los compuestos representativos de la presente invención y la invención se pueden sintetizar utilizando los intermedios apropiados, compuestos conocidos y reactivos.The compounds of the present invention and the description can be synthesized by various methods. Some of them are illustrated with reference to the schemes shown below. The schemes are for illustrative purposes, and the present invention and description are not limited to the chemical reactions and conditions shown therein. In the schemes shown below, some substituents may be omitted for clarity, but this is not intended to limit the description of the schemes. Representative compounds of the present invention and the invention can be synthesized using the appropriate intermediates, known compounds and reagents.
La producción del compuesto representado por la fórmula (I)The production of the compound represented by the formula (I)
El Esquema A muestra un método para producir el compuesto representado por la fórmula (I).Scheme A shows a method of producing the compound represented by the formula (I).
En los esquemas y métodos de producción generales a continuación, las definiciones de Ri y otras se muestran en cada sistema o método de producción general. R33 a R37 se definen de la siguiente manera:In the general production schemes and methods below, the definitions of Ri and others are shown in each general production system or method. R33 to R37 are defined as follows:
R33 representa grupo alquilo.R33 represents alkyl group.
5 R34 y R35 cada uno representa grupo alquilo. Alternativamente, una pluralidad de R34 o una pluralidad de R35 juntosR34 and R35 each represents alkyl group. Alternatively, a plurality of R34 or a plurality of R35 together
forman un anillo.They form a ring.
R36 representa grupo alquilo. Alternativamente, una pluralidad de R36 juntos forman un anillo.R36 represents alkyl group. Alternatively, a plurality of R36 together form a ring.
R37 representa grupo alquilo o arilo.R37 represents alkyl or aryl group.
Esquema AScheme A
10 El compuesto de fórmula (I) en la cual R1, R2, R3, y R4 se definen como en el compuesto representado por la fórmula (I) general mostrada anteriormente, se puede producir por el método descrito a continuación.The compound of formula (I) in which R1, R2, R3, and R4 are defined as in the compound represented by the general formula (I) shown above, can be produced by the method described below.
El 2-cetoacetonitrilo de fórmula (2) se obtiene a través de una reacción entre el éster del ácido carboxílico representado por la fórmula (1) y el anión de acetonitrilo que se genera permitiendo que una base actúe sobre el 15 acetonitrilo.The 2-ketoacetonitrile of formula (2) is obtained through a reaction between the carboxylic acid ester represented by formula (1) and the acetonitrile anion that is generated allowing a base to act on acetonitrile.
El compuesto representado por la fórmula (1) está disponible comercialmente o se puede preparar por medio de métodos conocidos en la técnica. Por ejemplo, ésteres del ácido carboxílico arilo/heteroarilo de fórmula (1) tales como éster etílico del ácido indol-2-carboxílico, éster etílico del ácido benzofurano-2-carboxílico, éster metílico del ácido benzotiofeno-2-carboxílico, éster metílico del ácido pirrol-2-carboxílico, y éster metílico del ácido quinolina-6- 20 carboxílico, están disponibles comercialmente. Otros compuestos se pueden preparar por calentamiento de los ácidos carboxílicos correspondientes en alcohol (R33OH) en presencia de un ácido (por ejemplo, ácido sulfúrico). Alternativamente, el éster metílico de fórmula (1), en el cual R33 es un grupo metilo, se puede preparar mediante una reacción con trimetilsilildiazometano o diazometano en un solvente (por ejemplo, diclorometano o metanol).The compound represented by the formula (1) is commercially available or can be prepared by methods known in the art. For example, esters of the aryl / heteroaryl carboxylic acid of formula (1) such as indole-2-carboxylic acid ethyl ester, benzofuran-2-carboxylic acid ethyl ester, benzothiophene-2-carboxylic acid methyl ester, methyl ester of Pyrrol-2-carboxylic acid, and quinoline-6- 20 carboxylic acid methyl ester, are commercially available. Other compounds may be prepared by heating the corresponding carboxylic acids in alcohol (R33OH) in the presence of an acid (for example, sulfuric acid). Alternatively, the methyl ester of formula (1), in which R33 is a methyl group, can be prepared by a reaction with trimethylsilyldiazomethane or diazomethane in a solvent (for example, dichloromethane or methanol).
El compuesto de fórmula (2) se puede preparar por medio de métodos conocidos en la técnica. Se puede preparar 25 mediante el tratamiento de acetonitrilo con una base (por ejemplo, diisopropilamida de litio o n-butil litio) y a continuación haciendo reaccionar el anión de acetonitrilo resultante con éster del ácido arilo/heteroarilo carboxílico.The compound of formula (2) can be prepared by methods known in the art. It can be prepared by treating acetonitrile with a base (for example, lithium diisopropylamide or n-butyl lithium) and then reacting the resulting acetonitrile anion with aryl / carboxylic heteroaryl ester.
El compuesto de fórmula (3) se puede preparar por medio de métodos conocidos en la técnica. El 2-ceto-3- dimetilamino-acrilonitrilo de fórmula (3) se puede preparar haciendo reaccionar el 2-cetoaceton¡tr¡lo de fórmula (2) con N,N-d¡met¡lformamida dimetil acetal en un solvente (por ejemplo, tolueno o tetrahidrofurano).The compound of formula (3) can be prepared by methods known in the art. The 2-keto-3-dimethylamino-acrylonitrile of the formula (3) can be prepared by reacting the 2-ketoacetontril of the formula (2) with N, N-dimethylformamide dimethyl acetal in a solvent (for example, toluene or tetrahydrofuran).
30 El compuesto de fórmula (4) se puede preparar por medio de métodos conocidos en la técnica. El 2-ceto-3-alcox¡- acrilonitrilo de fórmula (4) se puede preparar haciendo reaccionar el 2-cetoacetonitrilo de fórmula (2) y trialquil ortoformiato en un solvente (por ejemplo, acetonitrilo, cloroformo, o anhídrido acético) con calor.The compound of formula (4) can be prepared by methods known in the art. The 2-keto-3-alkoxy acrylonitrile of formula (4) can be prepared by reacting the 2-ketoacetonitrile of formula (2) and trialkyl orthoformate in a solvent (eg, acetonitrile, chloroform, or acetic anhydride) with heat .
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El compuesto de fórmula (I) se puede preparar por medio de métodos conocidos en la técnica. El 5-amino- cetopirazol de fórmula (I) se puede preparar haciendo reaccionar el 2-ceto-3-dimetilamino-acrilonitrilo de fórmula (3) con bencimidazol-5-ll hldrazina de fórmula (5) en presencia o ausencia de una base (por ejemplo, trietilamina o piridina) en un solvente (por ejemplo, etanol o N,N-dimetilacetamida); o haciendo reaccionar 2-ceto-3-alcoxi- acrilonitrilo de fórmula (4) con bencimidazol-5-il hidrazina de fórmula (5) o un compuesto en el cual la hidrazina en fórmula (5) se ha protegido (por ejemplo, N- benzhidrilideno - N’-(2-metil-1H-bencimidazol-5-il)-hidrazina, tert-butil éster del ácido N’-(2-metil-1H-bencimidazol-5-il)-hidrazina carboxílico, o tert-butil éster del ácido N-ferf- butoxicarbonil-N’-(2-metil-1H-bencimidazol-5-il)-hidrazina carboxílico), en presencia o ausencia de una base (por ejemplo, trietilamina o piridina) en un solvente (por ejemplo, etanol o N,N-dimetilacetamida).The compound of formula (I) can be prepared by methods known in the art. The 5-amino-cetopyrazole of formula (I) can be prepared by reacting the 2-keto-3-dimethylamino-acrylonitrile of formula (3) with benzimidazol-5-11 hldrazine of formula (5) in the presence or absence of a base (for example, triethylamine or pyridine) in a solvent (for example, ethanol or N, N-dimethylacetamide); or by reacting 2-keto-3-alkoxy acrylonitrile of formula (4) with benzimidazol-5-yl hydrazine of formula (5) or a compound in which the hydrazine in formula (5) has been protected (eg, N - benzhydrylidene - N '- (2-methyl-1 H -benzimidazol-5-yl) -hydrazine, tert-butyl ester of N' - (2-methyl-1 H -benzimidazol-5-yl) -hydrazine carboxylic acid, or tert -butyl ester of N-ferf-butoxycarbonyl-N '- (2-methyl-1H-benzimidazol-5-yl) -hydrazine carboxylic acid), in the presence or absence of a base (for example, triethylamine or pyridine) in a solvent (for example, ethanol or N, N-dimethylacetamide).
Cuando se sintetizan los compuestos con el anillo A que tiene un grupo NH, tal como indol o pirrol, en algunos casos, se utiliza un éster de fórmula (1) para formar un anillo de aminopirazol a través de las reacciones de fórmula (3) o (4) y la fórmula (5), y luego la desprotección se lleva a cabo para dar la fórmula (I) con el anillo A teniendo un grupo NH.When the compounds are synthesized with the A ring having an NH group, such as indole or pyrrole, in some cases, an ester of formula (1) is used to form an aminopyrazole ring through the reactions of formula (3) or (4) and formula (5), and then deprotection is carried out to give formula (I) with ring A having an NH group.
Los grupos protectores para indol incluyen los grupos arilsulfonilo (por ejemplo, grupo bencenosulfonilo y grupo toluenosulfonilo).Protecting groups for indole include arylsulfonyl groups (for example, benzenesulfonyl group and toluenesulfonyl group).
La fórmula (1) en la que el anillo A es un anillo indol protegido por un grupo arilsulfonilo se puede obtener haciendo reaccionar la fórmula (I) en la cual el anillo A es un indol desprotegido con arilsulfonil cloruro (por ejemplo, haluro de bencilo o haluro de p-metoxibencilo) en un solvente (por ejemplo, tetrahidrofurano o dimetilformamida) en presencia de una base (por ejemplo, hidruro de sodio o diisopropiletilamina).Formula (1) in which ring A is an indole ring protected by an arylsulfonyl group can be obtained by reacting formula (I) in which ring A is an indole deprotected with arylsulfonyl chloride (eg, benzyl halide or p-methoxybenzyl halide) in a solvent (for example, tetrahydrofuran or dimethylformamide) in the presence of a base (for example, sodium hydride or diisopropylethylamine).
Los grupos protectores para pirrol incluyen grupos bencilo (por ejemplo, grupo bencilo y grupo p-metoxibencilo). La fórmula (1) en el cual A es un anillo de pirrol protegido por un grupo bencilo se puede obtener haciendo reaccionar la fórmula (I) en la cual A es un pirrol desprotegido con haluro de bencilo (por ejemplo, cloruro de bencilo, bromuro de bencilo, o bromuro de 4-metoxibencilo) en un solvente (por ejemplo, tetrahidrofurano o dimetilformamida).Pyrrole protecting groups include benzyl groups (eg, benzyl group and p-methoxybenzyl group). The formula (1) in which A is a pyrrole ring protected by a benzyl group can be obtained by reacting the formula (I) in which A is a pyrrole deprotected with benzyl halide (eg, benzyl chloride, bromide of benzyl, or 4-methoxybenzyl bromide) in a solvent (for example, tetrahydrofuran or dimethylformamide).
Si el compuesto de fórmula (1) con Ri o R2 deseados, no está disponible comercialmente, es posible sintetizar un éster de fórmula (1) que tiene los Ri o R2 deseados por uno cualquiera de métodos (a) a (y) descritos a continuación, y luego sintetizar la fórmula (I) por el mismo método como en el esquema A. Alternativamente, el compuesto de fórmula (I) con un sustltuyente convertible en Ri o R2 se puede sintetizar y a continuación convertir en el compuesto con el sustltuyente Ri o R2 deseado.If the compound of formula (1) with desired Ri or R2 is not commercially available, it is possible to synthesize an ester of formula (1) having the desired Ri or R2 by any one of methods (a) to (and) described at then, and then synthesize formula (I) by the same method as in scheme A. Alternatively, the compound of formula (I) with a substituent convertible into Ri or R2 can be synthesized and then converted into the compound with the substituent Ri or R2 desired.
La conversión del sustltuyente R1 o R2 se puede lograr, mediante uno cualquiera de los métodos (a) a (y) descritos a continuación.The conversion of the substituent R1 or R2 can be achieved, by any one of the methods (a) to (y) described below.
1 (R1=OR5)1 (R1 = OR5)
Método (a)Method (a)
Cuando Ri es un éter (-OR5), el compuesto de fórmula (I) se puede preparar a través de la reacción de Mitsunobu entre alcohol (R5OH) y el compuesto de fórmula (6) en el cual R1 es un grupo hidroxilo, o a través de la esterificación en presencia de una base entre el compuesto de fórmula (6) en el cual R1 es un grupo hidroxilo y R5X que tiene un grupo saliente X, tal como halógeno o un grupo alquilsulfoniloxi.When Ri is an ether (-OR5), the compound of formula (I) can be prepared through the Mitsunobu reaction between alcohol (R5OH) and the compound of formula (6) in which R1 is a hydroxyl group, or through esterification in the presence of a base between the compound of formula (6) in which R1 is a hydroxyl group and R5X having a leaving group X, such as halogen or an alkylsulfonyloxy group.
4646
Alternativamente, un éster de fórmula (1) en la cual Ri es éter (-OR5) se puede preparar mediante la reacción de Mitsunobu entre alcohol (R5OH) y un éster de fórmula (7) en la cual R1 tiene un grupo hidroxilo, o a través de esterificación en presencia de una base entre el éster de fórmula (7) y R5X que tiene un grupo saliente X, tal como halógeno o un grupo alquilsulfoniloxi.Alternatively, an ester of formula (1) in which Ri is ether (-OR5) can be prepared by the reaction of Mitsunobu between alcohol (R5OH) and an ester of formula (7) in which R1 has a hydroxyl group, or through esterification in the presence of a base between the ester of formula (7) and R5X having a leaving group X, such as halogen or an alkylsulfonyloxy group.
5 El éster de fórmula (1) en la cual R1 es éter (-OR5) se puede utilizar para preparar el compuesto de fórmula (I) en la cual R1 es éter (-OR5) por el mismo método como en el esquema A.The ester of formula (1) in which R1 is ether (-OR5) can be used to prepare the compound of formula (I) in which R1 is ether (-OR5) by the same method as in Scheme A.
En general, la reacción de Mitsunobu se puede llevar a cabo utilizando alcohol (R5OH) y un compuesto que tiene un grupo hidroxilo, en un solvente (por ejemplo, tetrahidrofurano o dioxano) en presencia de un compuesto azo (por ejemplo, dietil azodicarboxilato o diisopropil azodicarboxilato), fosfina (por ejemplo, trifenilfosfina o tri-n-butilfosfina).In general, the Mitsunobu reaction can be carried out using alcohol (R5OH) and a compound having a hydroxyl group, in a solvent (e.g., tetrahydrofuran or dioxane) in the presence of an azo compound (e.g., diethyl azodicarboxylate or diisopropyl azodicarboxylate), phosphine (for example, triphenylphosphine or tri-n-butylphosphine).
10 En general, la esterificación se puede llevar a cabo por el calentamiento de un compuesto que tiene un grupo hidroxilo y R5X que tiene un grupo saliente X, tal como halógeno o grupo alquilsulfoniloxi, en un solvente (por ejemplo, dimetilformamida o tetrahidrofurano) en presencia de una base (por ejemplo, hidruro de sodio o carbonato de potasio).In general, the esterification can be carried out by heating a compound having a hydroxyl group and R5X having a leaving group X, such as halogen or alkylsulfonyloxy group, in a solvent (for example, dimethylformamide or tetrahydrofuran) in presence of a base (for example, sodium hydride or potassium carbonate).
15 Método (b)15 Method (b)
El compuesto de fórmula (I) en la cual R1 es un grupo amino (NR6R7) se puede preparar haciendo reaccionar el compuesto de fórmula (8) que tiene halógeno con una amina (NR6R7) a temperatura ambiente o con calor en presencia de una base (por ejemplo, carbonato de cesio, fe/f-butóxido de sodio, o fosfato de potasio) y un ligando (por ejemplo, N,N-dimetilglicina, 1,10-fenantrolina, o tri-ferí-butilfosfina) en un solvente (por ejemplo, dimetilsulfóxido, 20 dimetilformamida, tolueno, o dioxano) utilizando un catalizador de cobre (por ejemplo, yoduro de cobre) o catalizador de paladlo (por ejemplo, acetato de paladio).The compound of formula (I) in which R1 is an amino group (NR6R7) can be prepared by reacting the compound of formula (8) having halogen with an amine (NR6R7) at room temperature or with heat in the presence of a base (for example, cesium carbonate, fe / f-sodium butoxide, or potassium phosphate) and a ligand (for example, N, N-dimethylglycine, 1,10-phenanthroline, or tri-feri-butylphosphine) in a solvent (for example, dimethylsulfoxide, dimethylformamide, toluene, or dioxane) using a copper catalyst (for example, copper iodide) or palladium catalyst (for example, palladium acetate).
OHCOHC
HH
R8'N'R9R8'N'R9
OHC-OHC-
R2R2
R3R3
HH
R8'N'R9R8'N'R9
R2 v |u _ klR2 v | u _ kl
(I) R4 H(I) R4 H
(R1=CH,NR8R9)(R1 = CH, NR8R9)
R1R1
O-R.O-R.
3333
O-R,O-R,
R2R2
(R1=CH2NR8R9)(R1 = CH2NR8R9)
El compuesto de fórmula (I) en la cual Ri es un grupo amlnometllo (-(CRsRsOnZ-i, R8=R9=H) se puede preparar a través de aminadón reductora entre amina (NHRsRsi) y el compuesto de fórmula (9) que tiene un grupo aldehido. Alternativamente, un éster de fórmula (1) en la cual Rf es un grupo aminometilo (-(CR8Rg)„Zi, R8=R9=H) se puede preparar a través de aminación reductora entre amina (NHR8Rg) y un éster de fórmula (10) que tiene un grupo 5 aldehido. El compuesto de fórmula (I) en la cual Ri es un grupo aminometilo (-(CR8Rg)nZi, R8=R9=H) se puede obtener por el mismo método como en el esquema A, utilizando el éster de fórmula (1) en la cual Ri es un grupo aminometilo (-(CR8Rg)nZi, R8=Rg=H).The compound of formula (I) in which Ri is an amlnomethyl group (- (CRsRsOnZ-i, R8 = R9 = H) can be prepared through amine reducing aminadon (NHRsRsi) and the compound of formula (9) which it has an aldehyde group Alternatively, an ester of formula (1) in which Rf is an aminomethyl group (- (CR8Rg) „Zi, R8 = R9 = H) can be prepared through amine reductive amination (NHR8Rg) and an ester of formula (10) having an aldehyde group 5. The compound of formula (I) in which Ri is an aminomethyl group (- (CR8Rg) nZi, R8 = R9 = H) can be obtained by the same method as in scheme A, using the ester of formula (1) in which Ri is an aminomethyl group (- (CR8Rg) nZi, R8 = Rg = H).
En general, la aminación reductora se puede llevar a cabo con aldehido y amina (NHR8Rg) utilizando un agente de reducción (por ejemplo, triacetoxiborohidruro de sodio, cianoborohidruro de sodio, o borohidruro de sodio) en un 10 solvente (por ejemplo, diclorometano, 1,2-dicloroetano, o metanol), en presencia de un ácido (por ejemplo, ácido acético) en algunos casos, a partir de 0°C a temperatura ambiente.In general, reductive amination can be carried out with aldehyde and amine (NHR8Rg) using a reducing agent (e.g., sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride) in a solvent (e.g., dichloromethane, 1,2-dichloroethane, or methanol), in the presence of an acid (for example, acetic acid) in some cases, from 0 ° C to room temperature.
(R1=CONR12R13)(R1 = CONR12R13)
Método (d)Method (d)
El compuesto de fórmula (I) en la cual Ri es una amida (CONR12R13) se puede preparar haciendo reaccionar el 15 ácido carboxílico de fórmula (11) con una amina (NHR12R13) en presencia de un agente de condensación.The compound of formula (I) in which Ri is an amide (CONR12R13) can be prepared by reacting the carboxylic acid of formula (11) with an amine (NHR12R13) in the presence of a condensing agent.
En general, la síntesis de amida se puede lograr mediante la conversión de un ácido carboxílico en haluro de acilo o éster activado utilizando un agente de halogenación (por ejemplo, cloruro de tionilo o cloruro de oxalilo) o un activador (por ejemplo, cloroformiato de etilo), respectivamente, y luego hacerlo reaccionar con una amina (NHR12R13) en un solvente (por ejemplo, tetrahidrofurano, dimetilformamida, o diclorometano).In general, the synthesis of amide can be achieved by converting a carboxylic acid into acyl halide or activated ester using a halogenating agent (for example, thionyl chloride or oxalyl chloride) or an activator (for example, chloroformate ethyl), respectively, and then reacting it with an amine (NHR12R13) in a solvent (for example, tetrahydrofuran, dimethylformamide, or dichloromethane).
20 Alternativamente, la síntesis de amida se logra mediante la síntesis de un éster activo a partir del ácido carboxílico utilizando un agente de condensación (por ejemplo, diciclohexilcarbodiimida) en presencia de una base (por ejemplo, trietilamina) en un solvente (por ejemplo, tetrahidrofurano, dimetilformamida, o diclorometano), y a continuación el tratamiento del éster activo resultante con una amina (NHR12R13).Alternatively, the synthesis of amide is achieved by the synthesis of an active ester from the carboxylic acid using a condensing agent (for example, dicyclohexylcarbodiimide) in the presence of a base (for example, triethylamine) in a solvent (for example, tetrahydrofuran, dimethylformamide, or dichloromethane), and then the treatment of the resulting active ester with an amine (NHR12R13).
R3R3
1one
(R1=SR14)(R1 = SR14)
El compuesto de fórmula (I) en la cual Ri es sulfuro (-SR14) se puede preparar haciendo reaccionar tiol con el compuesto de fórmula (8) que tiene halógeno en presencia de una base (por ejemplo, carbonato de cesio, hexametlldlsllazlda de litio o fosfato de potasio) y un catalizador (por ejemplo, yoduro de cobre, o acetato de paladio) en un solvente (por ejemplo, dimetiisulfóxido o 1,2-dimetoxletano) con calor.The compound of formula (I) in which Ri is sulfide (-SR14) can be prepared by reacting thiol with the compound of formula (8) which has halogen in the presence of a base (for example, cesium carbonate, lithium hexamelldlsllazlda or potassium phosphate) and a catalyst (for example, copper iodide, or palladium acetate) in a solvent (for example, dimethisulfoxide or 1,2-dimethoxylethane) with heat.
5 El éster de fórmula (1) en la cual R1 es sulfuro (-SR-m) se puede preparar haciendo reaccionar tiol con el éster de fórmula (12) que tiene halógeno en presencia de una base (por ejemplo, carbonato de cesio, hexametildisilazlda de litio o fosfato de potasio) y un catalizador (por ejemplo, yoduro de cobre, o acetato de paladio) en un solvente (por ejemplo, dimetiisulfóxido o 1,2-dlmetoxietano) con calentamiento.The ester of formula (1) in which R 1 is sulfide (-SR-m) can be prepared by reacting thiol with the ester of formula (12) having halogen in the presence of a base (eg cesium carbonate, lithium hexamethyldisilazlda or potassium phosphate) and a catalyst (for example, copper iodide, or palladium acetate) in a solvent (for example, dimethisulfoxide or 1,2-dlmethoxyethane) with heating.
Alternativamente, el éster de fórmula (1) se puede preparar haciendo reaccionar el éster de fórmula (12) con una 10 base (por ejemplo, n-butll litio) a una temperatura baja (-80 a 0°C) en un solvente (por ejemplo, dietil éter o tetrahldrofurano), y luego hacerlo reaccionar con alquilsulfuro o dlalqulldlsulfuro. El éster de fórmula (1) en la cual R1 es sulfuro (-SR14) se puede utilizar para preparar el compuesto de fórmula (I) en la cual R1 es sulfuro (-SR14) por el mismo método como en el esquema A.Alternatively, the ester of formula (1) can be prepared by reacting the ester of formula (12) with a base (for example, n-butll lithium) at a low temperature (-80 to 0 ° C) in a solvent ( for example, diethyl ether or tetrahydrofuran), and then make it react with alkylsulfide or dlalqulldlsulfide. The ester of formula (1) in which R1 is sulfide (-SR14) can be used to prepare the compound of formula (I) in which R1 is sulfide (-SR14) by the same method as in Scheme A.
15 Método (f)15 Method (f)
El compuesto de fórmula (I) en la cual R1 es sulfóxldo (-SO2R15) se puede preparar mediante el tratamiento del compuesto de fórmula (13) que tiene un grupo sulfuro (-SR15) con un agente oxidante (por ejemplo, ácido m- cloroperbenzolco, oxon, o peróxido de hidrógeno) en un solvente (por ejemplo, diclorometano, metanol, o agua).The compound of formula (I) in which R1 is sulfoxide (-SO2R15) can be prepared by treating the compound of formula (13) having a sulfide group (-SR15) with an oxidizing agent (for example, m- acid chloroperbenzolco, oxon, or hydrogen peroxide) in a solvent (for example, dichloromethane, methanol, or water).
20 Método (g)20 Method (g)
El compuesto de fórmula (I) en la cual R1 es sulfona (-SO2R16) se puede preparar mediante el tratamiento del compuesto de fórmula (14) que tiene sulfuro (-SR16) con un agente oxidante (por ejemplo, ácido m-cloroperbenzoico, oxon, o peróxido de hidrógeno) en un solvente (por ejemplo, diclorometano, metanol, o agua).The compound of formula (I) in which R1 is sulfone (-SO2R16) can be prepared by treating the compound of formula (14) having sulfide (-SR16) with an oxidizing agent (eg, m-chloroperbenzoic acid, oxon, or hydrogen peroxide) in a solvent (for example, dichloromethane, methanol, or water).
El éster de fórmula (1) en la cual Ri es sulfona (-SO2R16), se puede preparar mediante el tratamiento del sulfuro de fórmula (15) con un agente oxidante (por ejemplo, ácido m-cloroperbenzoico, oxon, o peróxido de hidrógeno) en un solvente (por ejemplo, diclorometano, metanol, o agua). El éster de fórmula (1) en la cual ya que R1 es sulfona (- SO2R16) se puede utilizar para preparar el compuesto de fórmula (I) en la cual R1 es sulfona (-SO2R16) por el mismo 5 método como en el esquema A.The ester of formula (1) in which Ri is sulfone (-SO2R16), can be prepared by treating the sulfide of formula (15) with an oxidizing agent (eg, m-chloroperbenzoic acid, oxon, or hydrogen peroxide ) in a solvent (for example, dichloromethane, methanol, or water). The ester of formula (1) in which since R1 is sulfone (-SO2R16) can be used to prepare the compound of formula (I) in which R1 is sulfone (-SO2R16) by the same method as in the scheme TO.
(R1=NR17S02R18)(R1 = NR17S02R18)
(R1=NR17SO>R18)(R1 = NR17SO> R18)
HNR17S02R18 R1HNR17S02R18 R1
"0C,"0C,
R2R2
(R1=NR17SQ,R18)(R1 = NR17SQ, R18)
R17R17
HH
R2R2
1717
R18S02XR18S02X
R1R1
R2R2
LL
1one
Método (h)Method (h)
El compuesto de fórmula (I) en la cual R1 es alquilsufonamida (-NR17SO2R18) se puede preparar haciendo reaccionar el compuesto de fórmula (8) en la cual R1 es halógeno con alquilo o arilsufonamida (HNR17SO2R18) en presencia de 10 un metal tal como cobre. Alternativamente, se puede preparar haciendo reaccionar el compuesto de fórmula (16) que tiene un grupo amino (-NHR17) con un alquilo o haluro de arilsulfonilo.The compound of formula (I) in which R1 is alkylsufonamide (-NR17SO2R18) can be prepared by reacting the compound of formula (8) in which R1 is halogen with alkyl or arylsufonamide (HNR17SO2R18) in the presence of a metal such as copper. Alternatively, it can be prepared by reacting the compound of formula (16) having an amino group (-NHR17) with an alkyl or arylsulfonyl halide.
Alternativamente, el éster de fórmula (1) en la cual R1 es alquilsufonamida (-NR17SO2R18) se puede preparar haciendo reaccionar el éster de fórmula (12) que tiene halógeno con alquilo o arilsufonamida (HNR17SO2R18) en presencia de un metal tal como cobre. Alternativamente, se puede preparar haciendo reaccionar el éster de fórmula 15 (17) que tiene un grupo amino (-NHR17) con alquilo, haluro de arilsulfonilo, o semejantes. El éster de fórmula (1) enAlternatively, the ester of formula (1) in which R1 is alkylsufonamide (-NR17SO2R18) can be prepared by reacting the ester of formula (12) having halogen with alkyl or arylsufonamide (HNR17SO2R18) in the presence of a metal such as copper. Alternatively, it can be prepared by reacting the ester of formula 15 (17) having an amino group (-NHR17) with alkyl, arylsulfonyl halide, or the like. The ester of formula (1) in
la cual R1 es alquilsufonamida (-NR17SO2R18) se puede utilizar para preparar el compuesto de fórmula (I) en la cual R1 es alquilsufonamida (-NR17SO2R18) por el mismo método como en el esquema A.which R1 is alkylsufonamide (-NR17SO2R18) can be used to prepare the compound of formula (I) in which R1 is alkylsufonamide (-NR17SO2R18) by the same method as in Scheme A.
En general, la síntesis a partir de un compuesto de halógeno se logra haciendo reaccionar un compuesto de halógeno con alquilo o arllsufonamlda en presencia de una base (por ejemplo, carbonato de cesio o fosfato de potasio), un catalizador (por ejemplo, acetato de paladlo o yoduro de cobre), y, en algunos casos, un ligando (por ejemplo, tri-t-butllfosfina o N,N dimetllgllclna) en un solvente (por ejemplo, dloxano, tolueno, o dlmetilformamlda) con 5 calentamiento.In general, synthesis from a halogen compound is achieved by reacting a halogen compound with alkyl or arllsufonamide in the presence of a base (for example, cesium carbonate or potassium phosphate), a catalyst (for example, acetate copper palladium or iodide), and, in some cases, a ligand (for example, tri-t-butllphosphine or N, N dimethyllchnane) in a solvent (for example, dloxane, toluene, or dlmethylformamlda) with heating.
En general, la síntesis a partir de un compuesto de amina se logra haciendo reaccionar un compuesto de amina con alquilo o haluro de arllsulfonilo en presencia de una base (por ejemplo, trietilamina) en un solvente (por ejemplo, diclorometano).In general, the synthesis from an amine compound is achieved by reacting an amine compound with arllsulfonyl alkyl or halide in the presence of a base (for example, triethylamine) in a solvent (for example, dichloromethane).
Ar-B(OH)L, oAr-B (OH) L, or
HetAr-B(OH^HetAr-B (OH ^
----------------------------------------------------
N ONO
y-R3y-R3
H Ar-B(OR34)2 o HetAr-B(OR35^H Ar-B (OR34) 2 or HetAr-B (OR35 ^
(R1=ArO HetAr)(R1 = ArO HetAr)
Ar-BfOH^ oAr-BfOH ^ o
HetAr-B(OH),HetAr-B (OH),
--------------------------------------------------
OOR
Ar-B(OR34)2 o HetAr-BíORSSJjAr-B (OR34) 2 or HetAr-BíORSSJj
1one
(R1=Aro HetAr)(R1 = HetAr ring)
10 Método (i)10 Method (i)
El compuesto de fórmula (I) en la cual Ri es arilo o heteroarilo se puede preparar mediante la reacción de acoplamiento de Suzuki entre el compuesto de fórmula (8) que tiene halógeno y ácido arilborónico, ácido heteroaril borónico, éster del ácido arilborónico, o éster del ácido heteroaril borónico.The compound of formula (I) in which Ri is aryl or heteroaryl can be prepared by the Suzuki coupling reaction between the compound of formula (8) having halogen and arylboronic acid, heteroaryl boronic acid, arylboronic acid ester, or heteroaryl boronic acid ester.
Alternativamente, el éster de fórmula (1) en la cual Ri es arilo o heteroarilo se puede preparar a través de la reacción 15 de acoplamiento de Suzuki entre el éster de fórmula (12) que tiene halógeno y ácido arilborónico, ácido heteroaril borónico, éster del ácido arilborónico, o éster del ácido heteroaril borónico. El éster de fórmula (1) en la cual Ri es arilo o heteroarilo se pueden utilizar para preparar el compuesto de fórmula (I) en la cual Ri es arilo o heteroarilo por el mismo método como en el esquema A.Alternatively, the ester of formula (1) in which Ri is aryl or heteroaryl can be prepared through the Suzuki coupling reaction between the ester of formula (12) having halogen and arylboronic acid, heteroaryl boronic acid, ester of arylboronic acid, or ester of heteroaryl boronic acid. The ester of formula (1) in which Ri is aryl or heteroaryl can be used to prepare the compound of formula (I) in which Ri is aryl or heteroaryl by the same method as in Scheme A.
En general, la reacción de acoplamiento de Suzuki se lleva a cabo mediante el calentamiento de haluro de arilo o 20 haluro de heteroarilo junto con ácido arilborónico, ácido heteroaril borónico, éster del ácido arilborónico, o éster del ácido heteroaril borónico en presencia de una base (por ejemplo, fosfato de potasio o carbonato de cesio) y un catalizador (por ejemplo, acetato de paladio o tetrakistrifenilfosfina) en un solvente (por ejemplo, dioxano o tolueno).In general, the Suzuki coupling reaction is carried out by heating aryl halide or heteroaryl halide together with arylboronic acid, heteroaryl boronic acid, arylboronic acid ester, or heteroaryl boronic acid ester in the presence of a base (for example, potassium phosphate or cesium carbonate) and a catalyst (for example, palladium acetate or tetrakistriphenylphosphine) in a solvent (for example, dioxane or toluene).
Método (j)Method (j)
El compuesto de fórmula (I) en la cual Ri es un grupo ciano se puede preparar haciendo reaccionar el compuesto de fórmula (8) que tiene halógeno (X) con un cianuro tal como cianuro de cobre.The compound of formula (I) in which Ri is a cyano group can be prepared by reacting the compound of formula (8) having halogen (X) with a cyanide such as copper cyanide.
5 En general, la cianación se lleva a cabo mediante el calentamiento de un compuesto de halógeno, compuesto de alquilsulfonlloxi, o compuesto de arilsulfoniloxi junto con un agente de cianación (por ejemplo, cianuro de cobre (I) o cianuro de potasio) en un solvente (por ejemplo, dimetilformamida o N-metilpirrolidona).In general, cyanation is carried out by heating a halogen compound, alkylsulfonylloxy compound, or arylsulfonyloxy compound together with a cyanation agent (for example, copper (I) cyanide or potassium cyanide) in a solvent (for example, dimethylformamide or N-methylpyrrolidone).
Ácido alquilborónicoAlkylboronic acid
(R1=alquilo)(R1 = alkyl)
Método (k)Method (k)
10 El compuesto de fórmula (I) en la cual Ri es un grupo alquilo se puede preparar a través de la reacción de Suzuki entre el compuesto de fórmula (8) que tiene halógeno y ácido alquilborónico, éster del ácido alquilborónico, o un complejo de alquilo-trifluoruro de boro.The compound of formula (I) in which Ri is an alkyl group can be prepared through the Suzuki reaction between the compound of formula (8) having halogen and alkylboronic acid, alkylboronic acid ester, or a complex of boron alkyl trifluoride.
El éster de fórmula (1) en la cual Ri es un grupo alquilo se puede preparar a través de la reacción de Suzuki entre el éster de fórmula (12) que tiene halógeno y ácido alquilborónico, éster del ácido alquilborónico, o un complejo de 15 alquilo-trifluoruro de boro. El éster de fórmula (1) en la cual Ri es un grupo alquilo se puede utilizar para preparar el compuesto de fórmula (I) en la cual Ri es un grupo alquilo por el mismo método como en el esquema A.The ester of formula (1) in which Ri is an alkyl group can be prepared through the Suzuki reaction between the ester of formula (12) having halogen and alkylboronic acid, alkylboronic acid ester, or a complex of 15 boron alkyl trifluoride. The ester of formula (1) in which Ri is an alkyl group can be used to prepare the compound of formula (I) in which Ri is an alkyl group by the same method as in Scheme A.
En general, la reacción de Suzuki se lleva a cabo mediante el calentamiento de una mezcla de un compuesto de halógeno, un derivado de boro (por ejemplo, ácido alquilborónico, éster del ácido alquilborónico, o complejo de alquilo-trifluoruro de boro), y una base (por ejemplo, carbonato de potasio o fosfato de potasio) en un solvente (por 20 ejemplo, xileno, tolueno, dimetilformamida, dioxano, o tetrahidrofurano) en presencia de un catalizador de paladio (por ejemplo, acetato de paladio) y, en algunos casos, un ligando (por ejemplo, trifenilfosfina).In general, the Suzuki reaction is carried out by heating a mixture of a halogen compound, a boron derivative (for example, alkyl boronic acid, alkyl boronic acid ester, or boron alkyl trifluoride complex), and a base (for example, potassium carbonate or potassium phosphate) in a solvent (for example, xylene, toluene, dimethylformamide, dioxane, or tetrahydrofuran) in the presence of a palladium catalyst (for example, palladium acetate) and, in some cases, a ligand (for example, triphenylphosphine).
Agente perfluaroalquilantePerfluaroalkylating agent
NN
VR3VR3
NN
(R1 = perfluoroalqmlo)(R1 = perfluoroalqmlo)
R2R2
LL
Agente perfluoroalquilantePerfluoroalkylating agent
1212
R1R1
R2R2
1one
(R1 = perfluoroalquilo)(R1 = perfluoroalkyl)
Método (I)Method (I)
El compuesto de fórmula (I) en la cual Ri es un grupo perfluoroalquilo se puede preparar haciendo reaccionar el compuesto de fórmula (8) que tiene halógeno con un agente perfluoroalquilante.The compound of formula (I) in which Ri is a perfluoroalkyl group can be prepared by reacting the compound of formula (8) having halogen with a perfluoroalkylating agent.
5 El áster de fórmula (12) en la cual Ri es un grupo perfluoroalquilo se puede preparar haciendo reaccionar el áster de fórmula (11) que tiene halógeno con un agente perfluoroalquilante. El áster de fórmula (1) en la cual Ri es un grupo perfluoroalquilo se puede utilizar para preparar el compuesto de fórmula (I) en la cual Ri es un grupo perfluoroalquilo por el mismo método como en el esquema A.The ester of formula (12) in which Ri is a perfluoroalkyl group can be prepared by reacting the ester of formula (11) having halogen with a perfluoroalkylating agent. The ester of formula (1) in which Ri is a perfluoroalkyl group can be used to prepare the compound of formula (I) in which Ri is a perfluoroalkyl group by the same method as in Scheme A.
En general, la perfluoroalqullación se logra haciendo reaccionar un compuesto de halógeno, cobre (por ejemplo, 10 cobre o yoduro de cobre (I)), un agente perfluoroalquilante (tales como perfluoroalquilo de potasio carboxilato, trietilsililo perfluoroalquilo, o yoduro de perfluoroalquilo) en un solvente (por ejemplo, dimetilsulfóxido o dimetilformamida) con calor.In general, perfluoroalkullation is achieved by reacting a halogen compound, copper (for example, 10 copper or copper iodide (I)), a perfluoroalkylating agent (such as perfluoroalkyl potassium carboxylate, triethylsilyl perfluoroalkyl, or perfluoroalkyl iodide) in a solvent (for example, dimethylsulfoxide or dimethylformamide) with heat.
^—R3^ —R3
HH
55
1010
15fifteen
20twenty
2525
El compuesto de fórmula (I) en la cual R1 es un grupo alqulnllo se puede preparar a través de la reacción de Sonogashira del compuesto de fórmula (8) que tiene halógeno.The compound of formula (I) in which R 1 is an alkyl group can be prepared through the Sonogashira reaction of the compound of formula (8) having halogen.
El áster de fórmula (1) en la cual Ri es un grupo alquinilo se puede preparar mediante la reacción de Sonogashira del áster de fórmula (12) que tiene halógeno. El áster de fórmula (1) en la cual Ri es un grupo alqulnllo, se puede utilizar para preparar el compuesto de fórmula (I) en la cual Ri es un grupo alquinilo por el mismo método como en el esquema A.The ester of formula (1) in which Ri is an alkynyl group can be prepared by the Sonogashira reaction of the ester of formula (12) having halogen. The ester of formula (1) in which Ri is an alkylene group, can be used to prepare the compound of formula (I) in which Ri is an alkynyl group by the same method as in Scheme A.
En general, la reacción de Sonogashira se lleva a cabo haciendo reaccionar haluro de arilo o haluro de heteroarilo con un agente de alquinilación (por ejemplo, trimetilsililacetileno) en presencia de una base (por ejemplo, trietilamina o carbonato de potasio), un catalizador de cobre (por ejemplo, yoduro de cobre(l)), y un catalizador de paladio (por ejemplo, bis(trifenilfosfina)paladio dicloruro) en un solvente (por ejemplo, tetrahidrofurano o tolueno) con calor.In general, the Sonogashira reaction is carried out by reacting aryl halide or heteroaryl halide with an alkylating agent (for example, trimethylsilylacetylene) in the presence of a base (for example, triethylamine or potassium carbonate), a catalyst of copper (for example, copper iodide (l)), and a palladium catalyst (for example, bis (triphenylphosphine) palladium dichloride) in a solvent (for example, tetrahydrofuran or toluene) with heat.
(R1 =COOH)(R1 = COOH)
1212
R1R1
R2R2
LL
1one
(R1=COOH)(R1 = COOH)
Método (n)Method (n)
El compuesto de fórmula (I) en la cual Ri es un grupo carboxilo se puede preparar mediante una reacción para la introducción de monóxido de carbono en el compuesto de fórmula (8) que tiene halógeno.The compound of formula (I) in which Ri is a carboxyl group can be prepared by a reaction for the introduction of carbon monoxide into the compound of formula (8) having halogen.
El áster de fórmula (1) en la cual Ri es un grupo carboxilo se puede preparar mediante una reacción para introducir el monóxido de carbono en el áster de fórmula (12) que tiene halógeno. El éster de fórmula (1) en la cual Ri es un grupo carboxilo se puede proteger en el grupo carboxilo (por ejemplo, fert-butil éster) y a continuación utilizar para preparar el compuesto de fórmula (I) en la cual Ri es un grupo carboxilo por el mismo método como en el esquema A.The ester of formula (1) in which Ri is a carboxyl group can be prepared by a reaction to introduce carbon monoxide into the ester of formula (12) having halogen. The ester of formula (1) in which Ri is a carboxyl group can be protected in the carboxyl group (for example, fert-butyl ester) and then used to prepare the compound of formula (I) in which Ri is a group carboxyl by the same method as in scheme A.
En general, la introducción de monóxido de carbono se logra haciendo reaccionar haluro de arilo o haluro de heteroarilo en presencia de una base (por ejemplo, trietilamina o carbonato de sodio), un catalizador de paladio (por ejemplo, acetato de paladio), y un ligando (por ejemplo, trifenilfosfina) en un solvente (por ejemplo, dimetilsulfóxido o agua) bajo una atmósfera de monóxido de carbono. Alternativamente, la introducción se logra haciendo reaccionar haluro de arilo o haluro de heteroarilo con una base (por ejemplo, n-butil litio) en un solvente (por ejemplo, éter dietílico o tetrahidrofurano) a una temperatura baja (-80 a 0°C), y a continuación haciendo reaccionar monóxido de carbono con el mismo.In general, the introduction of carbon monoxide is achieved by reacting aryl halide or heteroaryl halide in the presence of a base (for example, triethylamine or sodium carbonate), a palladium catalyst (for example, palladium acetate), and a ligand (for example, triphenylphosphine) in a solvent (for example, dimethylsulfoxide or water) under an atmosphere of carbon monoxide. Alternatively, the introduction is achieved by reacting aryl halide or heteroaryl halide with a base (for example, n-butyllithium) in a solvent (for example, diethyl ether or tetrahydrofuran) at a low temperature (-80 to 0 ° C ), and then reacting carbon monoxide with it.
Método (o)Method (o)
El compuesto de fórmula (I) en la cual Ri es un grupo hidroxilo se puede preparar a través de la desalquilación del compuesto de fórmula (18) que tiene un grupo metoxi o grupo benciloxi.The compound of formula (I) in which Ri is a hydroxyl group can be prepared through the dealkylation of the compound of formula (18) having a methoxy group or benzyloxy group.
En general, la desmetllaclón del grupo metoxi se logra haciendo reaccionar una mezcla de un compuesto metoxi y un solvente (por ejemplo, diclorometano) con un ácido de Lewis (por ejemplo, trifluoruro de boro o cloruro de aluminio). Alternativamente, la desmetilación se logra haciendo reaccionar el compuesto metoxi en presencia de clorhidrato de piridina con calentamiento.In general, the demellaclone of the methoxy group is achieved by reacting a mixture of a methoxy compound and a solvent (for example, dichloromethane) with a Lewis acid (for example, boron trifluoride or aluminum chloride). Alternatively, demethylation is achieved by reacting the methoxy compound in the presence of pyridine hydrochloride with heating.
En general, la desbencllaclón del grupo benciloxi se logra a través de una reacción en presencia de un catalizador (por ejemplo, paladlo sobre carbono o hidróxido de paladio) en un solvente (por ejemplo, metanol) bajo una atmósfera de hidrógeno.In general, the debencllaclón of the benzyloxy group is achieved through a reaction in the presence of a catalyst (for example, palladium on carbon or palladium hydroxide) in a solvent (for example, methanol) under a hydrogen atmosphere.
Hetcíclico-B(OH^Heticyclic-B (OH ^
Hetcíclico-B(OR36^Hetcrylic-B (OR36 ^
(R1 =heterociclilo)(R1 = heterocyclyl)
R2R2
O" ^33O "^ 33
Hetcíclico-B(OHJHeticyclic-B (OHJ
Hetcíclico-B(OR36^Hetcrylic-B (OR36 ^
1212
1one
(R1=heterociclilo)(R1 = heterocyclyl)
Método (p)Method (p)
El compuesto de fórmula (I) en la cual Ri es un heteroclclllo alifático se puede preparar mediante la reacción de acoplamiento de Suzuki del compuesto de fórmula (8) que tiene halógeno con ácido borónico heterociclilo alifático o éster del ácido borónico heterociclilo alifático.The compound of formula (I) in which Ri is an aliphatic heterocycle can be prepared by the Suzuki coupling reaction of the compound of formula (8) having halogen with aliphatic heterocyclyl boronic acid or aliphatic heterocyclyl boronic acid ester.
El éster de fórmula (1) en la cual Ri es un heterociclilo alifático se puede preparar mediante la reacción de acoplamiento de Suzuki del éster de fórmula (12) que tiene halógeno con ácido borónico heterociclilo alifático o ésterThe ester of formula (1) in which Ri is an aliphatic heterocyclyl can be prepared by the Suzuki coupling reaction of the ester of formula (12) having halogen with boronic acid aliphatic heterocyclyl or ester
5555
del ácido borónico heterociclilo alifático. El áster resultante de fórmula (1) en la cual Ri es un heterociclilo allfátlco se puede utilizar para preparar el compuesto de fórmula (I) en la cual Ri es un heterociclilo alifático por el mismo método como en el esquema A.of the aliphatic heterocyclyl boronic acid. The resulting ester of formula (1) in which Ri is an all-alkyl heterocyclyl can be used to prepare the compound of formula (I) in which Ri is an aliphatic heterocyclyl by the same method as in Scheme A.
En general, la reacción de acoplamiento de Suzuki de heterociclilo alifático se logra haciendo reaccionar haluro de 5 arilo o haluro de heteroarilo con ácido borónico heterociclilo alifático o áster del ácido borónico heterociclilo alifático en presencia de una base (por ejemplo, fosfato de potasio) y un catalizador de paladio (por ejemplo, tetrakistrifenilfosfina) en un solvente (por ejemplo, dioxano o agua) con calor.In general, the Suzuki coupling reaction of aliphatic heterocyclyl is achieved by reacting 5-aryl halide or heteroaryl halide with aliphatic heterocyclyl boronic acid or ester of the aliphatic heterocyclyl boronic acid in the presence of a base (e.g., potassium phosphate) and a palladium catalyst (for example, tetrakistriphenylphosphine) in a solvent (for example, dioxane or water) with heat.
(R1 =OC(0)R21)(R1 = OC (0) R21)
Método (q)Method (q)
10 El compuesto de fórmula (I) en la cual Ri es aciloxi (-OC(0)R2i) se puede preparar a través de acilación entre el compuesto de fórmula (6) en la cual Ri es un grupo hidroxl y haluro de acilo o anhídrido carboxílico.The compound of formula (I) in which Ri is acyloxy (-OC (0) R2i) can be prepared by acylation between the compound of formula (6) in which Ri is a hydroxl and acyl halide group or carboxylic anhydride.
En general, la acilación del grupo hidroxilo se logra haciendo reaccionar un compuesto hidroxi y haluro de acilo o ácido carboxílico anhidro en presencia de una base (por ejemplo, trietilamina) en un solvente (por ejemplo, dlclorometano o piridina).In general, the acylation of the hydroxyl group is achieved by reacting a hydroxy compound and acyl halide or anhydrous carboxylic acid in the presence of a base (for example, triethylamine) in a solvent (for example, dichloromethane or pyridine).
15fifteen
(R1 =NR22C(0)R23)(R1 = NR22C (0) R23)
1one
(R1 =NR22C(0)R23)(R1 = NR22C (0) R23)
Método (r)Method (r)
El compuesto de fórmula (I) que tiene carbamida (-NR22C(0)R23) como R-i se puede preparar por medio de acilación del compuesto de fórmula (19) que tiene un grupo amino (-NHR22).The compound of formula (I) having carbamide (-NR22C (0) R23) as R-i can be prepared by acylation of the compound of formula (19) having an amino group (-NHR22).
20 El éster de fórmula (1) que tiene carbamida (-NR22C(0)R23) como R1 se puede preparar por medio de acilación del éster de fórmula (20) que tiene un grupo amino (-NHR22).The ester of formula (1) having carbamide (-NR22C (0) R23) as R1 can be prepared by acylation of the ester of formula (20) having an amino group (-NHR22).
En general, la acllación de un grupo arrimo se logra haciendo reaccionar un compuesto de amina con haluro de acilo o anhídrido carboxílico en presencia de una base (por ejemplo, trietilamina) en un solvente (por ejemplo, diclorometano o piridina). Alternativamente, la acllación se logra haciendo reaccionar un compuesto de amina con ácido carboxílico en presencia de una base (por ejemplo, trietilamina) y un agente de condensación (por ejemplo, 5 diciciohexilcarbodlimida) en un solvente (por ejemplo, tetrahidrofurano o diclorometano).In general, acylation of an arrimo group is achieved by reacting an amine compound with acyl halide or carboxylic anhydride in the presence of a base (eg, triethylamine) in a solvent (for example, dichloromethane or pyridine). Alternatively, the acylation is achieved by reacting an amine compound with carboxylic acid in the presence of a base (for example, triethylamine) and a condensing agent (for example, 5 dicyclohexylcarbodlimide) in a solvent (for example, tetrahydrofuran or dichloromethane).
(R1=C(Q)R19)(R1 = C (Q) R19)
Método (s)Method (s)
El compuesto de fórmula (I) que tiene aldehido (C(O)Rig; Rig=H) o cetona (C(O)Rig; Rig es distinto de H) como Ri se puede preparar mediante una reacción para Introducir de una fuente de carbonllo en el compuesto de fórmula (8) 10 que tiene halógeno.The compound of formula (I) having aldehyde (C (O) Rig; Rig = H) or ketone (C (O) Rig; Rig is different from H) as Ri can be prepared by a reaction to introduce from a source of carbonyl in the compound of formula (8) 10 which has halogen.
En general, en la síntesis de aldehido, la reacción para Introducir una fuente de carbonilo se logra mediante el calentamiento de un compuesto de halógeno en presencia de un catalizador (por ejemplo, acetato de paladio o tetrakis(trifenilfosfina) paladio), una base (por ejemplo, carbonato de sodio o trietilamina), y un agente de reducción (por ejemplo, trietilsilano) en un solvente (por ejemplo, tetrahidrofurano o N,N-d¡met¡lformam¡da), en una atmósfera 15 de monóxldo de carbono bajo presión ambiente o elevada. Mientras tanto, en la síntesis de la cetona, la reacción para Introducir una fuente de carbonllo, se logra utilizando aldehido, derivado de enol éter, derivado de hidrazona, o similares, en lugar de monóxldo de carbono, como una fuente de carbonilo.In general, in the synthesis of aldehyde, the reaction to introduce a carbonyl source is achieved by heating a halogen compound in the presence of a catalyst (for example, palladium acetate or tetrakis (triphenylphosphine) palladium), a base ( for example, sodium carbonate or triethylamine), and a reducing agent (for example, triethylsilane) in a solvent (for example, tetrahydrofuran or N, Ndmethylformamide), in a low carbon monoxide atmosphere 15 ambient or high pressure. Meanwhile, in the synthesis of the ketone, the reaction to introduce a carbonyl source is achieved using aldehyde, derived from enol ether, derived from hydrazone, or the like, instead of carbon monoxide, as a carbonyl source.
Alternativamente, la reacción se logra mediante intercambio de halógeno/metal de un compuesto de halógeno utilizando una base (por ejemplo, íerí-butil litio), seguido por la reacción con una fuente de carbonilo (por ejemplo, 20 N,N-dimetllformamida, N,N-dimetilalquilamida, o éster del ácido carboxílico).Alternatively, the reaction is achieved by halogen / metal exchange of a halogen compound using a base (for example, iron butyl lithium), followed by reaction with a carbonyl source (for example, 20 N, N-dimethylformamide, N, N-dimethylalkyl amide, or carboxylic acid ester).
Método (t)Method (t)
El compuesto de fórmula (I) que tiene tioamida (-NR24C(S)R25) como Ri se puede preparar mediante el tratamiento del compuesto de fórmula (21) que tiene amida (-NR24C(0)R25) con un agente de sulfuración (por ejemplo, reactivo 25 de Lawesson). Alternativamente, el compuesto de fórmula (I) se puede preparar mediante una reacción entre el compuesto de fórmula (22) que tiene un grupo amino (NHR24) y éster del ácido tiocarboxílico.The compound of formula (I) having thioamide (-NR24C (S) R25) as Ri can be prepared by treating the compound of formula (21) having amide (-NR24C (0) R25) with a sulfurizing agent ( for example, Lawesson's reagent 25). Alternatively, the compound of formula (I) can be prepared by a reaction between the compound of formula (22) having an amino group (NHR24) and thiocarboxylic acid ester.
En general, la tiocarbonllación se logra haciendo reaccionar, con calentamiento, un compuesto de carbamida con un agente de sulfuración (por ejemplo, reactivo de Lawesson) en un solvente (por ejemplo, tolueno).In general, thiocarbonylation is achieved by reacting, with heating, a carbamide compound with a sulfurizing agent (for example, Lawesson's reagent) in a solvent (for example, toluene).
La reacción entre el compuesto de fórmula (22) que tiene un grupo amino (NHR24) y éster del ácido tlocarboxíllco se logra haciendo reaccionar, con calentamiento, un compuesto de amina con éster del ácido tiocarboxílico en un 5 solvente (por ejemplo, metanol).The reaction between the compound of formula (22) having an amino group (NHR24) and tlocarboxylic acid ester is achieved by reacting, with heating, an amine compound with thiocarboxylic acid ester in a solvent (for example, methanol) .
Método (u)Method (u)
El compuesto de fórmula (I) que tiene tloamlda (-C(S)NR26R27) como R-i se puede preparar mediante el tratamiento del compuesto de fórmula (23) que tiene amida (-C(0)NR26R27) con un agente de sulfuración (por ejemplo, reactivo 10 de Lawesson). Alternativamente, el compuesto de fórmula (I) se puede preparar mediante una reacción entre un derivado de tioisoclanato y el compuesto de fórmula (8) que tiene halógeno.The compound of formula (I) having tloamlda (-C (S) NR26R27) as Ri can be prepared by treating the compound of formula (23) having amide (-C (0) NR26R27) with a sulfurizing agent ( for example, Lawesson's reagent 10). Alternatively, the compound of formula (I) can be prepared by a reaction between a thioisocyanate derivative and the compound of formula (8) having halogen.
En general, la tiocarbonllación se logra haciendo reaccionar, con calentamiento, un compuesto de carbamida con un agente de sulfuración (por ejemplo, reactivo de Lawesson) en un solvente (por ejemplo, tolueno).In general, thiocarbonylation is achieved by reacting, with heating, a carbamide compound with a sulfurizing agent (for example, Lawesson's reagent) in a solvent (for example, toluene).
En general, la reacción con un derivado de tioisocianato se lleva a cabo por el tratamiento de un compuesto de 15 halógeno con una base (por ejemplo, t-butil litio) en un solvente (por ejemplo, tetrahidrofurano o éter dietílico) a una temperatura baja (por ejemplo, -80 a 0°C), y a continuación la reacción con un derivado de tioisocianato.In general, the reaction with a thioisocyanate derivative is carried out by treating a halogen compound with a base (for example, t-butyl lithium) in a solvent (for example, tetrahydrofuran or diethyl ether) at a temperature low (for example, -80 to 0 ° C), and then the reaction with a thioisocyanate derivative.
(R1=S02NR28R29)(R1 = S02NR28R29)
Método (v)Method (v)
El compuesto de fórmula (I) que tiene sulfonamida (-SO2NR28R29) como R1 se puede preparar por conversión del 20 compuesto de fórmula (24) que tiene ácido sulfónico en haluro de sulfonilo utilizando un agente de halogenaclón (porThe compound of formula (I) having sulfonamide (-SO2NR28R29) as R1 can be prepared by conversion of the compound of formula (24) having sulfonic acid into sulfonyl halide using a halogenaclone agent (by
ejemplo, cloruro de tionilo u oxicloruro de fósforo), seguido por la reacción con amina (NHR28R29) en presencia de una base (por ejemplo, trietilamina) en un solvente (por ejemplo, dlclorometano o plrldlna).for example, thionyl chloride or phosphorus oxychloride), followed by reaction with amine (NHR28R29) in the presence of a base (for example, triethylamine) in a solvent (for example, dichloromethane or plrldlna).
(R1=OSOjR30)(R1 = OSOjR30)
5 Método (w)5 Method (w)
El compuesto de fórmula (I) que tiene el éster del ácido sulfónico (-OSO2R30) como R1 se puede preparar haciendo reaccionar el compuesto de fórmula (6) que tiene un grupo hidroxilo con haluro de sulfonilo (R30SO2X) o anhídrido de ácido sulfónico ((R3oS02)0) en presencia de una base (por ejemplo, trietilamina, piridina, o hidruro de sodio) en un solvente (por ejemplo, diclorometano o dimetilformamida).The compound of formula (I) having the sulfonic acid ester (-OSO2R30) as R1 can be prepared by reacting the compound of formula (6) having a hydroxyl group with sulfonyl halide (R30SO2X) or sulfonic acid anhydride ( (R3oS02) 0) in the presence of a base (for example, triethylamine, pyridine, or sodium hydride) in a solvent (for example, dichloromethane or dimethylformamide).
1010
Método (x)Method (x)
El compuesto de fórmula (I) que tiene éster del ácido sulfónico (-SO3R31) como R1 se puede preparar haciendo reaccionar el compuesto de fórmula (25) que tiene haluro de sulfonilo como R1 con alcohol (R31OH) en presencia de 15 una base (por ejemplo, trietilamina o 4-dimetilaminopiridina) en un solvente (por ejemplo, diclorometano o éter dietílico).The compound of formula (I) having sulfonic acid ester (-SO3R31) as R1 can be prepared by reacting the compound of formula (25) having sulfonyl halide such as R1 with alcohol (R31OH) in the presence of a base ( for example, triethylamine or 4-dimethylaminopyridine) in a solvent (for example, dichloromethane or diethyl ether).
Alternativamente, el compuesto de fórmula (I) se puede preparar haciendo reaccionar el compuesto de fórmula (24) que tiene ácido sulfónico como R1 con alcohol (R31OH) en presencia de una base (por ejemplo, trietilamina, 4- dlmetllamlnoplridlna, o hidruro de sodio) o un catalizador (por ejemplo, cloruro de cobalto), en un solvente (por 20 ejemplo, dlclorometano o éter dietílico). Alternativamente, el compuesto de fórmula (I) se puede preparar haciendoAlternatively, the compound of formula (I) can be prepared by reacting the compound of formula (24) having sulfonic acid such as R1 with alcohol (R31OH) in the presence of a base (for example, triethylamine, 4- dlmetllamlnoplridlna, or hydride of sodium) or a catalyst (for example, cobalt chloride), in a solvent (for example, dichloromethane or diethyl ether). Alternatively, the compound of formula (I) can be prepared by making
reaccionar el compuesto de fórmula (24) que tiene ácido sulfónlco como Ri con un compuesto de halógeno (R31X) en un solvente (por ejemplo, acetonitrilo).reacting the compound of formula (24) having sulfonic acid such as Ri with a halogen compound (R31X) in a solvent (eg, acetonitrile).
5 Método (y)5 Method (y)
El compuesto de fórmula (I) que tiene un grupo trialquilsililo (-Si(R32)3) como R1 se puede preparar por medio de tratamiento del compuesto de fórmula (8) que tiene halógeno con una base (por ejemplo, n-butllo litio) en un solvente (por ejemplo, tetrahidrofurano) a una temperatura baja (-80 a 0°C), seguido por el tratamiento con haluro de trlalqulloThe compound of formula (I) having a trialkylsilyl group (-Si (R32) 3) as R1 can be prepared by treating the compound of formula (8) having halogen with a base (for example, n-butyl lithium ) in a solvent (for example, tetrahydrofuran) at a low temperature (-80 to 0 ° C), followed by treatment with trlalqullo halide
(XSi(R32)3).(XSi (R32) 3).
1010
R1—AR1 — A
R2R2
O R33Or R33
1one
(A = indol)(A = indole)
El éster de fórmula (1) que tiene indol como anillo A está disponible comercialmente, o se puede preparar por medio de métodos bien conocidos en la técnica, por ejemplo, los métodos (1) a (3) descritos a continuación.The ester of formula (1) having indole as ring A is commercially available, or can be prepared by methods well known in the art, for example, methods (1) to (3) described below.
Método (1)Method (1)
15 El indol de fórmula (27) que tiene un grupo alcoxlcarbonllo (C(0)0R33> se puede preparar por medio de alcoxicarbonilación del compuesto indol de fórmula (26) que es protegido por un grupo alquilsulfonllo o aril sulfonilo.The indole of formula (27) having an alkoxycarbonyl group (C (0) 0R33>) can be prepared by alkoxycarbonylation of the indole compound of formula (26) which is protected by an alkylsulfonyl or aryl sulfonyl group.
En general, la alcoxicarbonilación se logra haciendo reaccionar una base (por ejemplo, litio diisopropilamida) con el compuesto Indol de fórmula (26) que es protegido por un grupo alquilsulfonilo o aril sulfonilo, en un solvente (porIn general, alkoxycarbonylation is achieved by reacting a base (for example, lithium diisopropylamide) with the indole compound of formula (26) which is protected by an alkylsulfonyl or aryl sulfonyl group, in a solvent (by
ejemplo, tetrahidrofurano), y a continuación haciendo reaccionar este con una fuente de carbonilo (por ejemplo, cloroformiato de etilo).for example, tetrahydrofuran), and then reacting this with a carbonyl source (for example, ethyl chloroformate).
Método (2)Method (2)
5 El indol de fórmula (29) que tiene un grupo alcoxicarbonilo (C(0)0R33) se puede preparar de la siguiente manera: el éster de piruvato se hace reaccionar con el derivado de hidrazina de fórmula (28) en un solvente (por ejemplo, metanol o etanol) bajo una condición áclda (por ejemplo, en ácido clorhídrico o ácido acético) para producir un derivado de hidrazona; y este derivado de hidrazona se hace reaccionar en un solvente (por ejemplo, etanol, diclorometano, o tolueno) bajo una condición ácida (por ejemplo, en ácido clorhídrico o ácido metanosulfónico).The indole of formula (29) having an alkoxycarbonyl (C (0) 0R33) group can be prepared as follows: the pyruvate ester is reacted with the hydrazine derivative of formula (28) in a solvent (by eg, methanol or ethanol) under an acid condition (for example, in hydrochloric acid or acetic acid) to produce a hydrazone derivative; and this hydrazone derivative is reacted in a solvent (for example, ethanol, dichloromethane, or toluene) under an acidic condition (for example, in hydrochloric acid or methanesulfonic acid).
1010
Método (3)Method (3)
El Indol de fórmula (29) que tiene un grupo alcoxicarbonilo (C(0)0R33) se puede preparar por calentamiento del derivado o-etinil anilina de fórmula (30) en presencia de un catalizador (por ejemplo, acetato de cobre) en un 15 solvente (por ejemplo, dlcloroetano) como se describe en Hiroya, K. et al. (J. Org. Chem., 69, 1126, (2004)) o Hlroya, K. et al. (Tetrahedron Letters, 43, 1277, (2002)).The indole of formula (29) having an alkoxycarbonyl (C (0) 0R33) group can be prepared by heating the o-ethynyl aniline derivative of formula (30) in the presence of a catalyst (eg, copper acetate) in a Solvent (eg dichloroethane) as described in Hiroya, K. et al. (J. Org. Chem., 69, 1126, (2004)) or Hlroya, K. et al. (Tetrahedron Letters, 43, 1277, (2002)).
R1R1
ATO
R2R2
OOR
OROR
3333
1one
(A=azaindol)(A = azaindole)
El éster de fórmula (1) que tiene azaindol como anillo A está disponible comercialmente, o se puede preparar por medio de métodos bien conocidos en la técnica, por ejemplo, mediante los métodos (4) a (7) descritos a 20 continuación.The ester of formula (1) having azaindole as ring A is commercially available, or it can be prepared by methods well known in the art, for example, by the methods (4) to (7) described below.
-X-X
I NI N
OOR
OROR
3333
3232
Método (4)Method (4)
El azaindol de fórmula de (32) que tiene un grupo alcoxlcarbonilo (C(0)OR33) se puede preparar de la siguiente manera: el áster de piruvato se hace reaccionar con la aminohalopiridina de fórmula (31) en un solvente (por 5 ejemplo, piridina) como se describe en Lachance, N. et al., Síntesis, 15, 2571, (2005); y la enamina resultante se calienta en presencia de un catalizador de paladio (por ejemplo, tetrakis(trifenilfosfina)paladio) y una base (por ejemplo, diciclohexilmetilamina).Azaindole of the formula of (32) having an alkoxycarbonyl (C (0) OR33) group can be prepared as follows: the pyruvate ester is reacted with the aminohalopyridine of formula (31) in a solvent (for example , pyridine) as described in Lachance, N. et al., Synthesis, 15, 2571, (2005); and the resulting enamine is heated in the presence of a palladium catalyst (for example, tetrakis (triphenylphosphine) palladium) and a base (for example, dicyclohexylmethylamine).
Método (5)Method (5)
10 El azaindol de fórmula (32) que tiene un grupo alcoxicarbonilo (C(0)0R33) se puede preparar como se describe en Romanelli, M. N. et al., Arkivoc, 286, (2004) por síntesis del intermedio de fórmula (34) haciendo reaccionar éster del ácido oxálico con la metilnitropiridina de fórmula (33) en presencia de una base (etóxido de sodio o semejantes) en un solvente (por ejemplo, etanol); seguido por la reducción catalítica bajo una atmósfera de hidrógeno.Azaindole of formula (32) having an alkoxycarbonyl group (C (0) 0R33) can be prepared as described in Romanelli, MN et al., Arkivoc, 286, (2004) by synthesis of intermediate of formula (34) by reacting oxalic acid ester with the methylnitropyridine of formula (33) in the presence of a base (sodium ethoxide or the like) in a solvent (eg, ethanol); followed by catalytic reduction under an atmosphere of hydrogen.
15fifteen
I NI N
OOR
OROR
ííit
3535
3232
Método (6)Method (6)
El azaindol de fórmula (32) que tiene un grupo alcoxicarbonilo (C(0)0R33) se puede preparar por medio de la descomposición térmica del éster del ácido 2-azido-3-piridina acrílico de fórmula (35) en un solvente (por ejemplo, mesitileno) mediante calentamiento como se describe en Roy, P. J. et al., Síntesis, 16, 2751, (2005).Azaindole of formula (32) having an alkoxycarbonyl (C (0) 0R33) group can be prepared by thermal decomposition of the ester of acrylic 2-azido-3-pyridine acid of formula (35) in a solvent (by example, mesitylene) by heating as described in Roy, PJ et al., Synthesis, 16, 2751, (2005).
Método (7)Method (7)
El azaindol de fórmula (37) que tiene un grupo alcoxlcarbonilo (C(0)0R33) se puede preparar por medio de alcoxlcarbonilación del compuesto azaindol de fórmula (36) que es protegido por un grupo alquilsulfonllo o grupo 5 arllsulfonllo.Azaindole of formula (37) having an alkoxycarbonyl group (C (0) 0R33) can be prepared by means of alkoxycarbonylation of the azaindole compound of formula (36) which is protected by an alkylsulfonyl group or arylsulfonyl group.
En general, la alcoxlcarbonilación del azaindol en la posición 2 se logra de la siguiente manera: una base (por ejemplo, diisopropilamida de litio) se hace reaccionar con el compuesto azaindol de fórmula (36) que está protegido por un grupo alquilsulfonilo o grupo arilsulfonilo, en un solvente (por ejemplo, tetrahidrofurano); y a continuación este se hace reaccionar con una fuente de carbonilo (por ejemplo, cloroformiato de etilo).In general, the alkoxycarbonylation of azaindole in position 2 is achieved as follows: a base (for example, lithium diisopropylamide) is reacted with the azaindole compound of formula (36) which is protected by an alkylsulfonyl group or arylsulfonyl group , in a solvent (for example, tetrahydrofuran); and then this is reacted with a carbonyl source (for example, ethyl chloroformate).
1010
ProPro
ii
3838
1one
(A=pirrol)(A = pyrrole)
El éster de fórmula (1) en la cual A es un anillo pirrol, y ya sea uno o ambos de Ri y R2 son grupo(s) arilo o heteroarilo, se puede preparar mediante la reacción de acoplamiento de Suzuki entre el monobromopirrol de fórmula (38) o dibromopirrol de fórmula (39), y ácido arilborónico, ácido heteroaril borónico, éster del ácido arilborónico, o éster del ácido heteroaril borónico.The ester of formula (1) in which A is a pyrrole ring, and either one or both of Ri and R2 are aryl or heteroaryl group (s), can be prepared by Suzuki coupling reaction between the monobromopyrrole of formula (38) or dibromopyrrole of formula (39), and arylboronic acid, heteroaryl boronic acid, arylboronic acid ester, or heteroaryl boronic acid ester.
NN
y1—R3y1 — R3
55
El bencimidazolil-5-hidrazina de fórmula (5) está disponible comercialmente, o se puede preparar por medio de métodos bien conocidos en la técnica, por ejemplo, mediante los métodos (8) a (11) descritos a continuación.The benzimidazolyl-5-hydrazine of formula (5) is commercially available, or can be prepared by methods well known in the art, for example, by the methods (8) to (11) described below.
55
1010
15fifteen
20twenty
2525
3030
3535
R4 H 5R4 H 5
R4R4
4444
npnp
HH
ProPro
4646
ProPro
4747
4444
4848
La bencimidazolil-5-hidrazma de fórmula (5) se puede preparar por medio de métodos bien conocidos en la técnica.The benzimidazolyl-5-hydrazma of formula (5) can be prepared by methods well known in the art.
El 5-nitrobencimidazol de fórmula (41) se prepara haciendo reaccionar la 4-nitro-1,2-fenilendiamina de fórmula (40) con ácido carboxílico (R3COOH), aldehido (R3CHO), triéster del ácido ortocarboxílico (RsC(OR)3), o haluro de acilo (R3COX) bajo una condición ácida (por ejemplo, en ácido clorhídrico o ácido sulfúrico), o en presencia de ácido de Lewis (por ejemplo, complejo trifluoruro de boro/éter dietílico o dicloro-oxo-zirconio (IV)), en un solvente (por ejemplo, metanol o xileno).The 5-nitrobenzimidazole of formula (41) is prepared by reacting the 4-nitro-1,2-phenylenediamine of formula (40) with carboxylic acid (R3COOH), aldehyde (R3CHO), orthocarboxylic acid triester (RsC (OR) 3 ), or acyl halide (R3COX) under an acidic condition (for example, in hydrochloric acid or sulfuric acid), or in the presence of Lewis acid (for example, boron trifluoride / diethyl ether complex or dichloro-oxo-zirconium ( IV)), in a solvent (for example, methanol or xylene).
El derivado de anilina de fórmula (42) se prepara por reducción catalítica del compuesto preparado de fórmula (41) bajo una atmósfera de hidrógeno en presencia de un catalizador (por ejemplo, paladio sobre carbono o hidróxido de paladio) en un solvente (por ejemplo, metanol o etanol).The aniline derivative of formula (42) is prepared by catalytic reduction of the compound prepared of formula (41) under a hydrogen atmosphere in the presence of a catalyst (for example, palladium on carbon or palladium hydroxide) in a solvent (for example , methanol or ethanol).
La 5-bezim¡dazol¡l-5-h¡drazina de fórmula (5) se prepara por la posterior diazotización bajo una condición ácida (por ejemplo, en ácido clorhídrico) y la reducción utilizando cloruro de estaño (II) o semejantes (por ejemplo, cloruro de estaño (II)). Mientras tanto, el 5-nltrobencimidazol de fórmula (41) también se puede preparar por nitración del bencimidazol de fórmula (43).The 5-bezim¡dazol¡l-5-hrazrazine of formula (5) is prepared by subsequent diazotization under an acidic condition (for example, in hydrochloric acid) and reduction using tin (II) chloride or the like ( for example, tin (II) chloride. Meanwhile, 5-nltrobenzimidazole of formula (41) can also be prepared by nitration of benzimidazole of formula (43).
Los grupos funcionales se pueden modificar, por ejemplo, por métodos descritos en "Smith and March, March’s Advanced Organic Chemlstry (Flfth ed., John Wiley & Sons, 2001)" o "Richard C. Larock, Comprehensive Organic Transformatlons (VCH Publlshers, Inc., 1989)". Los compuestos utilizados como un material para la producción pueden ser los disponibles comerclalmente, o según sea necesario, pueden ser producidos por métodos convencionales.Functional groups can be modified, for example, by methods described in "Smith and March, March's Advanced Organic Chemlstry (Flfth ed., John Wiley & Sons, 2001)" or "Richard C. Larock, Comprehensive Organic Transformatlons (VCH Publlshers, Inc., 1989). " The compounds used as a material for production may be those available commercially, or as necessary, may be produced by conventional methods.
Alternativamente, el compuesto de fórmula (46) se preparó mediante la introducción de un grupo protector en la unidad estructural bencimidazol de la 5-halobencimidazol de fórmula (44) en el sistema de reacción. El grupo protector utilizado es preferiblemente un grupo que se puede quitar fácilmente y de forma selectiva para la desprotección en las etapas posteriores. Los métodos de selección de grupos protectores y de desprotección se describen, por ejemplo, en Greene and Wuts, Protective Groups ¡n Organic Synthesis (thlrd ed., John Wiley & Sons, 1999). Los métodos se utilizan apropiadamente dependiendo de las condiciones de reacción. Por ejemplo, un grupo dlmetoxlmetllo, grupo trlmetllsllllo, grupo p-metoxibencllo, grupo tetrahidropiranilo, grupo formulo, grupo bencenosulfonllo o semejantes se pueden introducir como un grupo protector en condiciones ácldas o básicas. Cuando se Introduce un grupo protector, se utilizan preferiblemente los ácidos en un Intervalo de aproximadamente 1% a aproximadamente 1 equivalente.Alternatively, the compound of formula (46) was prepared by introducing a protective group into the benzimidazole structural unit of the 5-halobenzimidazole of formula (44) in the reaction system. The protective group used is preferably a group that can be easily and selectively removed for deprotection in the later stages. Protective and deprotection group selection methods are described, for example, in Greene and Wuts, Protective Groups in Organic Synthesis (thlrd ed., John Wiley & Sons, 1999). The methods are used appropriately depending on the reaction conditions. For example, a dlmethoxylmethyl group, trlmetllsllllo group, p-methoxybenzyl group, tetrahydropyranyl group, formula group, benzenesulfonyl group or the like can be introduced as a protective group under acrid or basic conditions. When a protecting group is introduced, acids are preferably used in an interval of about 1% to about 1 equivalent.
Los ácidos incluyen ácidos inorgánicos tales como ácido clorhídrico; ácido sulfúrico o ácidos sulfónicos tales como ácido toluenosulfónico; ácidos carboxílicos tales como ácido acético, ácido propiónico y ácido benzoico; sales de ácidos fuertes tales como toluenosulfonato de piridinio; y sustancias que generan ácido clorhídrico en el sistema de reacción, tales como cloruro de trlmetilsililo. Además de los ácidos de Brónsted anteriores, ácidos de Lewis talesAcids include inorganic acids such as hydrochloric acid; sulfuric acid or sulfonic acids such as toluenesulfonic acid; carboxylic acids such as acetic acid, propionic acid and benzoic acid; salts of strong acids such as pyridinium toluenesulfonate; and substances that generate hydrochloric acid in the reaction system, such as trlmethylsilyl chloride. In addition to the above Bronsted acids, Lewis acids such
Método (8)Method (8)
(Método 9)(Method 9)
55
1010
15fifteen
20twenty
2525
3030
3535
4040
45Four. Five
50fifty
5555
como haluros de metales, incluyendo cloruro de zinc, cloruro de magnesio, y cloruro de litio también se utilizan eficazmente en la reacción para introducir grupos protectores. Cuando se introduce un grupo protector, las bases se usan preferiblemente a un equivalente o más; o en algunos casos, en una cantidad en exceso tal como aproximadamente tres equivalentes. Las bases utilizadas preferiblemente incluyen hidruros metálicos tales como hidruro de sodio e hidruro de potasio; carbonatas de metales tales como carbonato de potasio y carbonato de cesio; y alcoholatos de metales tales como t-butóxido de potasio y t-butóxido de sodio.As metal halides, including zinc chloride, magnesium chloride, and lithium chloride are also effectively used in the reaction to introduce protecting groups. When a protecting group is introduced, the bases are preferably used to an equivalent or more; or in some cases, in an excess amount such as approximately three equivalents. The bases used preferably include metal hydrides such as sodium hydride and potassium hydride; carbonates of metals such as potassium carbonate and cesium carbonate; and metal alcoholates such as potassium t-butoxide and sodium t-butoxide.
A continuación, se adicionó una base para la reacción de intercambio de halógeno/metal para producir un intermedio en el que el grupo halógeno de fórmula (46) se sustituye con un metal. Alquil-litio o un haluro de alquil-magnesio se utiliza preferiblemente como la base. Las bases más preferidas incluyen haluros de alquilmagnesio inferior tales como cloruro de isopropilmagnesio, bromuro de isopropilmagnesio, cloruro de sec-butilmagnesio, y cloruro de ciclohexilmagnesio. Los solventes que aseguren la estabilidad de los reactivos de metal en el sistema de reacción se utilizan preferiblemente en la reacción de intercambio halógeno/metal. Los solventes incluyen, por ejemplo, solventes de éter tales como éter dietílico, dimetoxietano y tetrahidrofurano. Se prefiere una temperatura de reacción que asegura la estabilidad de los reactivos de metal en el sistema de reacción. Teniendo en cuenta las reacciones conocidas de intercambio halógeno/metal descritas en documentos, la temperatura preferida varía de aproximadamente -80 °C a la temperatura ambiente, más preferiblemente desde aproximadamente -78 °C a 15 °C. Las bases utilizadas en este documento son las soluciones disponibles comercialmente, o preparadas utilizando haluros de alquilo y litio metálico o de magnesio metálico. Un intermedio resultante de la sustitución del grupo halógeno de fórmula (46) con un metal se trata con un derivado de ácido azodicarboxílico (por ejemplo, diferí- butil éster del ácido azodicarboxílico o dietil éster del ácido azodicarboxílico) para obtener el compuesto de fórmula (47). Entonces, el grupo protector bencimidazol se retira para la desprotección para proporcionar la hidrazina protegida de fórmula (45). La hidrazina protegida de fórmula (45) se puede purificar y aislar de la solución de reacción como una forma libre o una sal con un ácido apropiado. Los ácidos apropiados incluyen no sólo los ácidos inorgánicos tales como ácido clorhídrico, ácido bromhídrico, y ácido sulfúrico, sino también los ácidos que son eficaces en la cristalización y purificación. Los ácidos incluyen, por ejemplo, ácidos sulfónicos tales como ácido metanosulfónico y ácido toluenosulfónico, y ácidos carboxílicos tales como ácido acético, ácido benzoico, ácido málico, ácido maleico, y ácido fumárico. Finalmente, el grupo protector hidrazina se retira para la desprotección para proporcionar la bencimidazolilo hidrazina de fórmula (5). La desprotección se puede llevar a cabo en condiciones ácidas o básicas conocidas descritas en los documentos. Los ácidos utilizados en la desprotección incluyen no sólo ácidos inorgánicos tales como ácido clorhídrico, ácido bromhídrico, y ácido sulfúrico, pero también ácidos fuertes que incluyen ácidos carboxílicos tales como ácido trifluoroacético y ácido pentafluoropropiónico, y ácidos sulfónicos tales como ácido metanosulfónico y ácido toluenosulfónico. Según sea necesario, la solución de reacción se puede diluir con un solvente apropiado, y la desprotección se puede llevar a cabo. Los solventes preferiblemente utilizados en este documento incluyen solventes de amida tales como DMF, DMA, y NMP. La benzoimidazolilo hidrazina de fórmula (5) de interés se puede producir mediante tratamiento en dicho solvente a una temperatura que varía desde aproximadamente temperatura enfriada con hielo hasta el punto de ebullición del solvente. Mientras tanto, las bases usadas adecuadamente en la desprotección incluyen hidróxidos de metales de alquilo tales como hidróxido de sodio e hidróxido de potasio, carbonatas de metal de alquilo tales como carbonato de sodio y carbonato de potasio. La hidrazina benzoimidazolilo de fórmula (5) de interés se puede producir mediante el tratamiento en presencia de dicha base en alcohol tal como metanol o etanol a una temperatura que oscila desde aproximadamente la temperatura enfriada con hielo hasta el punto de ebullición del solvente.Next, a base for the halogen / metal exchange reaction was added to produce an intermediate in which the halogen group of formula (46) is replaced with a metal. Alkyl lithium or an alkyl magnesium halide is preferably used as the base. The most preferred bases include lower alkyl magnesium halides such as isopropyl magnesium chloride, isopropyl magnesium bromide, sec-butyl magnesium chloride, and cyclohexyl magnesium chloride. Solvents that ensure the stability of metal reagents in the reaction system are preferably used in the halogen / metal exchange reaction. Solvents include, for example, ether solvents such as diethyl ether, dimethoxyethane and tetrahydrofuran. A reaction temperature that ensures the stability of the metal reagents in the reaction system is preferred. Taking into account the known halogen / metal exchange reactions described in documents, the preferred temperature ranges from about -80 ° C to room temperature, more preferably from about -78 ° C to 15 ° C. The bases used in this document are commercially available solutions, or prepared using metal halides of lithium and metal or of magnesium metal. An intermediate resulting from the substitution of the halogen group of formula (46) with a metal is treated with a derivative of azodicarboxylic acid (for example, differed di-butyl ester of azodicarboxylic acid or diethyl ester of azodicarboxylic acid) to obtain the compound of formula ( 47). Then, the benzimidazole protecting group is removed for deprotection to provide the protected hydrazine of formula (45). The protected hydrazine of formula (45) can be purified and isolated from the reaction solution as a free form or a salt with an appropriate acid. Appropriate acids include not only inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, but also acids that are effective in crystallization and purification. Acids include, for example, sulfonic acids such as methanesulfonic acid and toluenesulfonic acid, and carboxylic acids such as acetic acid, benzoic acid, malic acid, maleic acid, and fumaric acid. Finally, the hydrazine protecting group is removed for deprotection to provide the benzimidazolyl hydrazine of formula (5). The deprotection can be carried out under known acidic or basic conditions described in the documents. Acids used in deprotection include not only inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, but also strong acids that include carboxylic acids such as trifluoroacetic acid and pentafluoropropionic acid, and sulfonic acids such as methanesulfonic acid and toluenesulfonic acid. As necessary, the reaction solution can be diluted with an appropriate solvent, and deprotection can be carried out. The solvents preferably used herein include amide solvents such as DMF, DMA, and NMP. The benzoimidazolyl hydrazine of formula (5) of interest can be produced by treatment in said solvent at a temperature ranging from approximately ice-cold temperature to the boiling point of the solvent. Meanwhile, the bases used suitably in deprotection include hydroxides of alkyl metals such as sodium hydroxide and potassium hydroxide, alkyl metal carbonates such as sodium carbonate and potassium carbonate. The benzoimidazolyl hydrazine of formula (5) of interest can be produced by treating said base in alcohol such as methanol or ethanol at a temperature ranging from about the temperature cooled with ice to the boiling point of the solvent.
(Método 10)(Method 10)
Alternativamente, la unidad estructural de bencimidazol del 5-halobencimidazol de fórmula (44) se protege con un grupo protector descrito anteriormente en el sistema de reacción para proporcionar el compuesto de fórmula (46). A continuación, este se calienta en presencia de un derivado de hidrazina (por ejemplo, di-ferí-butiloxicarbonil hidrazina), una base (por ejemplo, carbonato de cesio o carbonato de potasio), un catalizador de metal de transición (por ejemplo, acetato de paladio, yoduro de cobre, o bromuro de cobre), un ligando (por ejemplo, trifenilfosfina, N, N- dimetil glicina, o N, N'-dimetil etilendiamina), en un solvente (por ejemplo, N, N-dimetilacetamida). De este modo, se obtiene el compuesto de fórmula (47). A continuación, el grupo protector bencimidazol se retira para la desprotección para proporcionar la hidrazina protegida de fórmula (45). Finalmente, el grupo protector de hidrazina se retira para la desprotección por el método como se describió anteriormente para proporcionar la bencimidazolil hidrazina de fórmula (5).Alternatively, the benzimidazole structural unit of the 5-halobenzimidazole of formula (44) is protected with a protecting group described above in the reaction system to provide the compound of formula (46). This is then heated in the presence of a hydrazine derivative (for example, di-feri-butyloxycarbonyl hydrazine), a base (for example, cesium carbonate or potassium carbonate), a transition metal catalyst (for example, palladium acetate, copper iodide, or copper bromide), a ligand (for example, triphenylphosphine, N, N-dimethyl glycine, or N, N'-dimethyl ethylenediamine), in a solvent (for example, N, N- dimethylacetamide). In this way, the compound of formula (47) is obtained. Next, the benzimidazole protecting group is removed for deprotection to provide the protected hydrazine of formula (45). Finally, the hydrazine protecting group is removed for deprotection by the method as described above to provide the benzimidazolyl hydrazine of formula (5).
Método (11)Method (11)
Alternativamente, el derivado de ácido borónico de fórmula (48) y un derivado de hidrazina (por ejemplo, di-ferí- butiloxicarbonil hidrazina o di-ferí-butil éster del ácido azodicarboxílico) se agita en presencia de una base (por ejemplo, tetrametil etilendiamina), un catalizador de cobre (por ejemplo, yoduro de cobre, fluoruro de cobre, o acetato de cobre) en un solvente (por ejemplo, metanol, tetrahidrofurano, o 1,2-dimetoxietano) bajo una atmósfera de nitrógeno o en el aire, a una temperatura comprendida desde aproximadamente la temperatura ambiente hasta el punto de ebullición del solvente. De este modo, se obtiene la hidrazina protegida de fórmula (45). Finalmente, elAlternatively, the boronic acid derivative of formula (48) and a hydrazine derivative (for example, di-ferrityl butyloxycarbonyl hydrazine or di-ferrityl butyl ester of azodicarboxylic acid) is stirred in the presence of a base (for example, tetramethyl ethylenediamine), a copper catalyst (for example, copper iodide, copper fluoride, or copper acetate) in a solvent (for example, methanol, tetrahydrofuran, or 1,2-dimethoxyethane) under a nitrogen atmosphere or in the air, at a temperature from about room temperature to the boiling point of the solvent. In this way, the protected hydrazine of formula (45) is obtained. Finally the
grupo protector hidrazina se retira para la desprotección por el método como se describió anteriormente para proporcionar la bencimidazolil hidrazina de fórmula (5).Hydrazine protecting group is removed for deprotection by the method as described above to provide the benzimidazolyl hydrazine of formula (5).
EjemplosExamples
La presente invención se describe más específicamente a continuación con referencia a los Ejemplos y ejemplos de 5 prueba, pero no se debe interpretar como limitada a los mismos. Todos los materiales iniciales y reactivos se obtuvieron a partir de proveedores comerciales o se sintetizaron por métodos conocidos. Por lo general, Los espectros 1H-RMN se obtuvieron mediante la medición, con o sin Me4Si como una referencia interna, utilizando EX270 (JEOL), Mercury300 (Varian), ECP-400 (JEOL), o 400-MR (Varían) (s = singlete; d = doblete; t = triplete; brs = singlete amplio; m= múltiple). Las mediciones de espectrometría de masas se llevaron a cabo utilizando el 10 espectrómetro de masas LCQ Clásica (Thermo Electron), ZQ2000 (Waters), o ZMD4000 (Waters). Se generaron microondas utilizando Initiator™ (Biotage).The present invention is described more specifically below with reference to the Examples and test examples, but should not be construed as limited thereto. All starting materials and reagents were obtained from commercial suppliers or synthesized by known methods. Typically, 1H-NMR spectra were obtained by measuring, with or without Me4Si as an internal reference, using EX270 (JEOL), Mercury300 (Varian), ECP-400 (JEOL), or 400-MR (They vary) ( s = singlet; d = doublet; t = triplet; brs = broad singlet; m = multiple). Mass spectrometry measurements were carried out using the LCQ Classic (Thermo Electron), ZQ2000 (Waters), or ZMD4000 (Waters) mass spectrometer. Microwaves were generated using Initiator ™ (Biotage).
[Ejemplo 1: Síntesis de [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(1H-indol-2-il)-metanona][Example 1: Synthesis of [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (1H-indole-2-yl) -methanone]
/ NH,/ NH,
L NL N
NN
II
NN
NN
HH
Una solución acuosa (1.67 mi) de hidróxido de sodio 4 M se adicionó a una solución en etanol (17 mi) de [5-am¡no-1- 15 (2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(1-bencenosulfonil-1H-indol-2-il) metanona (87 mg). La mezcla resultante se agitó a temperatura ambiente, durante 2 horas. La mezcla de reacción se vertió en agua. El sólido resultante se recolectó por filtración, se lavó con agua, y se secó para dar la [5-amino-1-(2-metil-1H-bencimidazol-5- ¡l)-1H-p¡razol-4-M]-(1H-¡ndol-2-¡l) metanona (40 mg, 63%).An aqueous solution (1.67 ml) of 4 M sodium hydroxide was added to a solution in ethanol (17 ml) of [5-amine-1- 15 (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (1-benzenesulfonyl-1H-indol-2-yl) methanone (87 mg). The resulting mixture was stirred at room temperature, for 2 hours. The reaction mixture was poured into water. The resulting solid was collected by filtration, washed with water, and dried to give [5-amino-1- (2-methyl-1H-benzimidazol-5-1l) -1 H -pyrazol-4-M ] - (1H-¡ndol-2-¡l) methanone (40 mg, 63%).
1H-RMN (DMSO-De) 8: 12.47 (1H, s), 11.70 (1H, s), 8.32 (1H, s), 7.70 (1H, d, J = 8.0 Hz), 7.66-7.55 (2H, m), 7.50- 20 7.45 (2H, m), 7.31-7.23 (2H, m), 7.10-7.06 (1H, m), 7.01 (2H, brs), 2.53 (3H, s) ESI (LC-MS modo positivo) m/z 3571H-NMR (DMSO-De) 8: 12.47 (1H, s), 11.70 (1H, s), 8.32 (1H, s), 7.70 (1H, d, J = 8.0 Hz), 7.66-7.55 (2H, m ), 7.50-20 7.45 (2H, m), 7.31-7.23 (2H, m), 7.10-7.06 (1H, m), 7.01 (2H, brs), 2.53 (3H, s) ESI (LC-MS positive mode ) m / z 357
[(M+H)+][(M + H) +]
[Ejemplo 1A][Example 1A]
Síntesis de [5-amino-1-(2-met¡l-3H-bencimidazol-5-¡l)-1H-pirazol-4-il]-(1H-indol-2-il)-metanona L-malatoSynthesis of [5-amino-1- (2-methyl-3H-benzimidazol-5-α) -1H-pyrazol-4-yl] - (1H-indole-2-yl) -methanone L-malate
25 Cantidades predeterminadas de ácido L-málico (68 g, 0.507 mol) y [5-amino-1-(2-metil-3H-bencimidazol-5-il)- IHpirazol- 4-¡l]-(1H-indol-2-il)-metanona hidrato (190 g, 0.507 mol) se disolvieron en sulfóxido de dimetilo (0.418 I, 2.2 v/peso) y acetona (0.418 I, 2.2 v/peso). A continuación, la solución resultante se filtró utilizando un Kiriyama rohto (filtro de papel No. 4), y se colocó en un matraz de separación de 10-L con una chaqueta. La solución de reacción se calentó a 50°C para disolución.25 Default amounts of L-malic acid (68 g, 0.507 mol) and [5-amino-1- (2-methyl-3H-benzimidazol-5-yl) -IHpirazol-4-l] - (1H-indole- 2-yl) -methanone hydrate (190 g, 0.507 mol) was dissolved in dimethyl sulfoxide (0.418 I, 2.2 v / weight) and acetone (0.418 I, 2.2 v / weight). Next, the resulting solution was filtered using a Kiriyama rohto (paper filter No. 4), and placed in a 10-L separation flask with a jacket. The reaction solution was heated at 50 ° C for dissolution.
30 Una cantidad predeterminada del ácido L-málico (544.4 g, 4.06 mol) se disolvió en acetona (1.25 I, 6.6 v/peso) y ácido acético (0.418 I, 2.2 v/peso). A continuación, la solución resultante se filtró utilizando un Kiriyama rohto (filtro de papel No. 4), y se colocó en un matraz de separación de 10-L con una chaqueta mientras se mantenía la temperatura interior a 45°C o más. El cristal de siembra (0.95 g, 0.5%) se suspendió en acetona (7.5 mi), y a continuación este se colocó en un matraz de separación de 10-L con una chaqueta.A predetermined amount of L-malic acid (544.4 g, 4.06 mol) was dissolved in acetone (1.25 I, 6.6 v / weight) and acetic acid (0.418 I, 2.2 v / weight). Next, the resulting solution was filtered using a Kiriyama rohto (paper filter No. 4), and placed in a 10-L separation flask with a jacket while maintaining the interior temperature at 45 ° C or more. The sowing glass (0.95 g, 0.5%) was suspended in acetone (7.5 ml), and then it was placed in a 10-L separation flask with a jacket.
Después de siete horas, la suspensión se enfrió a 25°C. Los cristales se recolectaron por filtración utilizando un Kiriyama rohto, y se lavó dos veces con acetona (0.85 I, 5 v/peso). El polvo húmedo resultante se colocó en un matraz de separación de 10-L con una chaqueta.After seven hours, the suspension was cooled to 25 ° C. The crystals were collected by filtration using a Kiriyama rohto, and washed twice with acetone (0.85 I, 5 v / weight). The resulting wet powder was placed in a 10-L separation flask with a jacket.
Se adicionó acetona (2.85 I, 15 v/peso) en el matraz, y la suspensión se agitó por tres horas a 50°C. Los cristales 5 resultantes se recolectaron por filtración utilizando un Kiriyama rohto, y se lavaron dos veces con acetona (0.85 I, 5 v/peso).Acetone (2.85 I, 15 v / weight) was added to the flask, and the suspension was stirred for three hours at 50 ° C. The resulting crystals were collected by filtration using a Kiriyama rohto, and washed twice with acetone (0.85 I, 5 v / weight).
El polvo húmedo resultante se secó, durante tres horas bajo presión reducida a una temperatura externa de 40°C para proveerThe resulting wet powder was dried, for three hours under reduced pressure at an external temperature of 40 ° C to provide
[5-amino-1-(2-metil-3H-bencimidazol-5-il)-1H-pirazol-4-il]-(1H-indol-2-il)-metanona L-malato (556.9 g, 73%).[5-amino-1- (2-methyl-3H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (1H-indole-2-yl) -methanone L-malate (556.9 g, 73% ).
10 1H-RMN (DMSO-D6) 6: 11.69 (1H, s), 8.31 (1H, s), 8.25-7.00 (10H, m), 4.25-4.22 (1H, m), 3.33 (2H, brs), 2.69-2.32 (9H, m)10 1H-NMR (DMSO-D6) 6: 11.69 (1H, s), 8.31 (1H, s), 8.25-7.00 (10H, m), 4.25-4.22 (1H, m), 3.33 (2H, brs), 2.69-2.32 (9H, m)
FAB modo positivo m/z 157.1, 232.1, 289.2, 357.2 [(M+H)+]FAB positive mode m / z 157.1, 232.1, 289.2, 357.2 [(M + H) +]
[Ejemplo 1B][Example 1B]
Síntesis de [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(1H-indol-2-il)-metanona clorhidratoSynthesis of [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (1H-indole-2-yl) -methanone hydrochloride
La [5-amlno-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-¡l]-(1H-indol-2-il)-metanona (194 mg) se disolvió en dimetilformamida (1.94 mi). Una solución acuosa de ácido clorhídrico 2 M (300 mi) se disolvió en cinco porciones y se adicionó gota a gota por separado a esta a 25°C. El 2-Propanol (4 mi) se disolvió en tres porciones y se adicionó por separado a la solución de reacción a intervalos de cinco minutos. El precipitado resultante se recolectó por 20 filtración, y se lavó con 2-propanol (1 mi). A continuación, el polvo se secó bajo presión reducida a 40°C. Esto produjo un polvo opalescente (188 mg, 88%).[5-Aml-1- (2-methyl-1H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (1 H -indole-2-yl) -methanone (194 mg) was dissolved in dimethylformamide (1.94 ml). An aqueous solution of 2M hydrochloric acid (300 ml) was dissolved in five portions and added separately dropwise thereto at 25 ° C. The 2-Propanol (4 ml) was dissolved in three portions and added separately to the reaction solution at five minute intervals. The resulting precipitate was collected by filtration, and washed with 2-propanol (1 mL). Then, the powder was dried under reduced pressure at 40 ° C. This produced an opalescent powder (188 mg, 88%).
11.72 (1H, s), 8.39 (1H, s), 7.96 (1H, d, J = 2.1 Hz), 7.92 (1H, d, J = 8.7 Hz), 7.71 (1H, t, J = 2.1 Hz), 7.68 (1H, t, J = 2.1 Hz), 7.51 (1H, s), 7.48 (1H, d, J = 2.1 Hz), 7.28 (1H, d, J = 7.6 Hz), 7.23 (3H, s), 7.09 (1H, t, J = 7.6 Hz), 2.82 (3H,11.72 (1H, s), 8.39 (1H, s), 7.96 (1H, d, J = 2.1 Hz), 7.92 (1H, d, J = 8.7 Hz), 7.71 (1H, t, J = 2.1 Hz), 7.68 (1H, t, J = 2.1 Hz), 7.51 (1H, s), 7.48 (1H, d, J = 2.1 Hz), 7.28 (1H, d, J = 7.6 Hz), 7.23 (3H, s), 7.09 (1H, t, J = 7.6 Hz), 2.82 (3H,
s).s).
25 ESI (LC-MS modo positivo) m/z 357 [(M+H)+]25 ESI (LC-MS positive mode) m / z 357 [(M + H) +]
[Ejemplo 1C][Example 1C]
Síntesis de [5-am¡no-1-(2-met¡l-1H-bencim¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(1H-¡ndol-2-¡l)-metanona 1-metanosulfonato monohldratoSynthesis of [5-am-1-1 (2-methyl-1H-benzimdadazol-5-l) -1H-p.razole-4-l] - (1H-lndol-2- L) -methanone 1-methanesulfonate monohydrate
4I4I
OOR
Una solución acuosa (64.9 mi) de ácido metanosulfónico 2 M se adicionó a una solución en dimetilformamida (420 mi) de [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(1H-indol-2-il)-metanona (42 g). Esta se agitó a temperatura ambiente, durante 20 minutos. A continuación, se adicionó metil-t-butil éter (105 mi) a la solución de reacción. Se adicionaron a esta 3.0 mg de un cristal de siembra, y esta se agitó a temperatura ambiente. Después 5 de la confirmación de la precipitación del cristal, se disolvió metil-t-butil éter (105 mi) en cuatro porciones y se adicionó por separado a la solución de reacción a intervalos de 15 minutos. La solución de reacción se agitó a temperatura ambiente, durante 1.5 horas. Los cristales resultantes se recolectaron por filtración utilizando un Kiriyama rohto. El sólido recolectado por filtración se lavó tres veces con metil-t-butil éter (210 mi), y se secó para proveer [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(1H-indol-2-il)-metanona 1- metanosulfonato 10 monohidrato (42.68 g, 84%).An aqueous solution (64.9 ml) of 2 M methanesulfonic acid was added to a solution in dimethylformamide (420 ml) of [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4 -il] - (1H-indole-2-yl) -methanone (42 g). This was stirred at room temperature for 20 minutes. Then, methyl-t-butyl ether (105 ml) was added to the reaction solution. To this 3.0 mg of a planting crystal was added, and it was stirred at room temperature. After confirmation of the precipitation of the crystal, methyl-t-butyl ether (105 ml) was dissolved in four portions and added separately to the reaction solution at 15 minute intervals. The reaction solution was stirred at room temperature for 1.5 hours. The resulting crystals were collected by filtration using a Kiriyama rohto. The solid collected by filtration was washed three times with methyl-t-butyl ether (210 ml), and dried to provide [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazole -4-yl] - (1H-indole-2-yl) -methanone 1- methanesulfonate monohydrate (42.68 g, 84%).
1H-RMN (DMSO-D6) 8: 11.70 (1H, s), 8.39 (1H, s), 7.99 (1H, d, J = 1.6 Hz), 7.94 (1H, d, J = 8.8 Hz), 7.74-7.68 (2H, m), 7.51-7.46 (2H, m), 7.29-7.18 (3H, m), 7.11-7.06 (1H, m), 2.84 (3H, s), 2.37 (3H, s)1H-NMR (DMSO-D6) 8: 11.70 (1H, s), 8.39 (1H, s), 7.99 (1H, d, J = 1.6 Hz), 7.94 (1H, d, J = 8.8 Hz), 7.74- 7.68 (2H, m), 7.51-7.46 (2H, m), 7.29-7.18 (3H, m), 7.11-7.06 (1H, m), 2.84 (3H, s), 2.37 (3H, s)
ESI (LC-MS modo positivo) m/z 357 [(M+H)+]ESI (LC-MS positive mode) m / z 357 [(M + H) +]
Los compuestos de los Ejemplos 2 a 35 enumerados en la Tabla 1, se sintetizaron mediante el mismo método como 15 en el Ejemplo 1.The compounds of Examples 2 to 35 listed in Table 1, were synthesized by the same method as in Example 1.
Tabla 1Table 1
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 2 2
- [5-amino-1-(2-metil-1 H- bencimidazol -5-il)- IHpirazol- 4-¡l]-(6- pirrolidin-1 -ilmetil-1 H-indol- 2-¡l)-metanona 440 1H-RMN (DMSO-D6) 8: 12.46 (1.0H, d, J = 3.9 Hz), 11.62 (1 .OH, s), 8.30 (1 .OH, d, J=4.9 Hz), 7.61 (3.0H, m), 7.41 (2.OH, m), 7.29 (1.0H, t, J = 7.3 Hz), 7.10-6.90 (3.OH, m), 3.66 (2.0H, s), 2.54 (3H, s), 2.48-2.42 (2.0H, m), 1.71 (4.0H, m). [5-amino-1- (2-methyl-1 H- benzimidazol -5-yl) - I-pyrazol-4-yl] - (6- pyrrolidin-1-ylmethyl-1 H-indole-2-l) - methanone 440 1H-NMR (DMSO-D6) 8: 12.46 (1.0H, d, J = 3.9 Hz), 11.62 (1 .OH, s), 8.30 (1 .OH, d, J = 4.9 Hz), 7.61 ( 3.0H, m), 7.41 (2.OH, m), 7.29 (1.0H, t, J = 7.3 Hz), 7.10-6.90 (3.OH, m), 3.66 (2.0H, s), 2.54 (3H , s), 2.48-2.42 (2.0H, m), 1.71 (4.0H, m).
- 3 3
- ^CTO^Cysc [5-amino-1-(2-metil-1 H- bencimidazol- 5-il)- 1 Hpirazol-4-il] -[6-(4- hidroxi-piperidin-1 -ilmetil) - 1 H-indol-2-ilj-metanona 470 1H-RMN (CD30D) 8: 8.27 (1.0H, s), 7.70-7.60 (3.OH, m), 7.44 (1.0H, s), 7.40-7.30 (2.OH, m), 7.11 (1.0H, dd, J = 8.1, 1.2 Hz), 3.64 (3.OH, m), 2.90- 2.80 (2H, m), 2.61 (3.0H, s), 2.30-2.20 (2.OH, m), 1.90-1.80 (2.0H, m), 1.65- 1.50 (2.OH, m). ^ CTO ^ Cysc [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 Hpirazol-4-yl] - [6- (4- hydroxy-piperidin-1-methylmethyl) - 1 H-indol-2-yl-methanone 470 1 H-NMR (CD30D) 8: 8.27 (1.0H, s), 7.70-7.60 (3.OH, m), 7.44 (1.0H, s), 7.40-7.30 (2 .OH, m), 7.11 (1.0H, dd, J = 8.1, 1.2 Hz), 3.64 (3.OH, m), 2.90-2.80 (2H, m), 2.61 (3.0H, s), 2.30-2.20 (2.OH, m), 1.90-1.80 (2.0H, m), 1.65-1.50 (2.OH, m).
- 4 4
- [5-amino-1-(2-metil-1 H- bencimidazol-5-il)- 1 Hpirazol-4-il] (1 Hpirrolo[3,2-c]piridin-2- il)-metanona 358 1H-RMN (CD30D) 8: 9.02-8.98 (1H, m), 8.31 (1H, s), 8.25 (1H, d, J = 5.9 Hz), 7.70-7.65 (2H, m), 7.59-7.56 (1H, m), 7.51 (1H, d. J = 5.9 Hz), 7.38 (1H, dd, J= 8.8, 2.0 Hz), 2.62 (3H, s). [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 Hpirazol-4-yl] (1 Hpyrrolo [3,2-c] pyridin-2- yl) -methanone 358 1H- NMR (CD30D) 8: 9.02-8.98 (1H, m), 8.31 (1H, s), 8.25 (1H, d, J = 5.9 Hz), 7.70-7.65 (2H, m), 7.59-7.56 (1H, m ), 7.51 (1H, d. J = 5.9 Hz), 7.38 (1H, dd, J = 8.8, 2.0 Hz), 2.62 (3H, s).
- 5 5
- [5-amino-1-(2-metil-1 H- bencimidazol-5-il)- 1 Hpirazol-4-il] -(6- piperazin-1 -il metil-1 H- indol-2-il)-metanona 455 1H-RMN (CD30D) 8: 8.27 (1 .OH, s), 7.74-7.68 (3.OH, m), 7.48-7.20 (20H, m), 7.36 (1 .OH, d, J = 1.0 Hz), 7.13 (1 OH, m), 3.74 (2.0H, m), 3.25-3.20 (4.OH, m), 2.77-2.70 (4.0H, m), 2.66 (3.OH, s), [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 Hpirazol-4-yl] - (6- piperazin-1-methyl-1 H- indole-2-yl) - methanone 455 1 H-NMR (CD30D) 8: 8.27 (1 .OH, s), 7.74-7.68 (3.OH, m), 7.48-7.20 (20H, m), 7.36 (1 .OH, d, J = 1.0 Hz), 7.13 (1 OH, m), 3.74 (2.0H, m), 3.25-3.20 (4.OH, m), 2.77-2.70 (4.0H, m), 2.66 (3.OH, s),
- Ejemplo Example
- Estructura Nombre del compuesto miz 1H-RMN Structure Name of compound miz 1H-NMR
- 6 6
- f'y-cV'r‘—P nii. i.-.- [5-am¡no-1-(2-met¡l- 1H-benc¡m¡dazol-5-¡l)- 1 Hpirazol-4-il] -[6-(2- morfoli n-4-il-etoxi)-1 H- ¡ndol-2-¡l]-metanona 486 1H-RMN (DMSO-D6) 5: 12.45 (1 OH, br s), 11.50 (1 .OH, br s), 8.27 (1 OH, s), 7.60-7.55 (3.OH, m), 7.40 (1 .OH, br s), 7.32-7.28 (1 .OH, m), 6.93 (3.0H, br s), 6.75 (1 .OH, dd, J = 8.8, 2.4 Hz), 4.11 (2.OH, t, J = 5.9 Hz), 3.60 (4.0H, t, J = 4.6 Hz), 3.34-3.28 (4.0H, m), 2.73 (2.OH, t, J = 5.9 Hz), 2.53 (3.0H, s)- f'y-cV'r‘ — P nii. i.-.- [5-am-n-1- (2-methyl-1H-benzyldazol-5-l) - 1 Hpirazol-4-yl] - [6- (2- morpholi n-4-yl-ethoxy) -1 H- ndol-2-l] -methanone 486 1 H-NMR (DMSO-D6) 5: 12.45 (1 OH, br s), 11.50 (1 .OH, br s ), 8.27 (1 OH, s), 7.60-7.55 (3.OH, m), 7.40 (1 .OH, br s), 7.32-7.28 (1 .OH, m), 6.93 (3.0H, br s) , 6.75 (1 .OH, dd, J = 8.8, 2.4 Hz), 4.11 (2.OH, t, J = 5.9 Hz), 3.60 (4.0H, t, J = 4.6 Hz), 3.34-3.28 (4.0H , m), 2.73 (2.OH, t, J = 5.9 Hz), 2.53 (3.0H, s) -
- 7 7
- ít-h&s [5-am¡no-1-(2-met¡l- 1H-benc¡m¡dazol- 5-¡l)- 1 Hpirazol-4-il] -[6- (tetrahidro-pi ran-4- ilox¡)-1 H-indol-2-il]- metanona 457 1H-RMN (DMSO-d6) 8: 12.46 (1 .OH, br s), 11.44 (1 .OH, br s), 8.27 (1 OH, s), 7.61-7.57 (3.OH, m), 7.39 (1 .OH, br s), 7.29 (1.0H, d, J = 8.3 Hz), 6.98- 6.95 (3.OH, m), 6.79 (1 .OH, d, J = 8.8 Hz), 4.59-4.53 (1 .OH, m), 3.90-3.85 (2.OH, m), 3.53-3.43 (2.0H, m), 2.53 (3.OH, s), 2.02-1.99 (2.0H, m), 1.68- 1.59 (2.OH, m). ít-h & s [5-am-n-1- (2-methyl-1H-benzyldazol-5-l) - 1 Hpyrazol-4-yl] - [6- (tetrahydro-pi ran- 4- ilox¡) -1 H-indole-2-yl] - methanone 457 1H-NMR (DMSO-d6) 8: 12.46 (1 .OH, br s), 11.44 (1 .OH, br s), 8.27 ( 1 OH, s), 7.61-7.57 (3.OH, m), 7.39 (1 .OH, br s), 7.29 (1.0H, d, J = 8.3 Hz), 6.98-6.95 (3.OH, m) , 6.79 (1 .OH, d, J = 8.8 Hz), 4.59-4.53 (1 .OH, m), 3.90-3.85 (2.OH, m), 3.53-3.43 (2.0H, m), 2.53 (3 .OH, s), 2.02-1.99 (2.0H, m), 1.68-1.59 (2.OH, m).
- 8 8
- ^ n * ° H [5-amino-1-(2-met¡l- 1H-benc¡m¡dazol- 5-¡l)- IHpirazol- 4-il] -(4- cloro-1 H-indol- 2-il)- metanona 391, 393 1H-RMN (DMSO-D6) 8: 12.49 (1H, s), 12.10 (1H, s), 8.32 (1H, d, J = 3.6 Hz), 7.66 (1H, dd, J = 4.9, 3.3 H), 7.58 (1H, J = 4.0 Hz), 7.47 (1H, d, J = 7.9 Hz), 7.32-7.31 (3H, m), 7.26 (1H, t, J = 7.7 Hz), 7.19 (1H, s), 7.16 (1H, s), 2.54 (3H, s). ^ n * ° H [5-amino-1- (2-methyl-1H-benzyldazol-5-l) - I-pyrazol-4-yl] - (4- chloro-1 H-indole- 2-yl) - methanone 391, 393 1H-NMR (DMSO-D6) 8: 12.49 (1H, s), 12.10 (1H, s), 8.32 (1H, d, J = 3.6 Hz), 7.66 (1H, dd , J = 4.9, 3.3 H), 7.58 (1H, J = 4.0 Hz), 7.47 (1H, d, J = 7.9 Hz), 7.32-7.31 (3H, m), 7.26 (1H, t, J = 7.7 Hz ), 7.19 (1H, s), 7.16 (1H, s), 2.54 (3H, s).
- 9 10 11 12 9 10 11 12
- H [5-am¡no-1-(2-metil- 1H-benc¡m¡dazol- 5-il)- 1 Hpirazol- 4-il] -(5- bromo-1 H-indol- 2-il)- metanona 435, 437 1H-RMN (DMSO-D6) 8: 12.48 (1H, s), 11.93 (1H, s), 8.28 (1H, s), 7.88 (1H, d, J = 1.5 Hz), 7.63-7.59 (2H, m), 7.47-7.44 (2H, m), 7.37 (1H, dd, J = 8.6, 1.9 Hz), 7.29 (1H, dd, J = 8.6, 1.9 Hz), 7.04 (2H, s), 2.54 (3H, s). H [5-amine-1- (2-methyl- 1 H -benzamdazol-5-yl) -1 Hpirazol-4-yl] - (5- bromo-1 H-indol-2-yl) - methanone 435, 437 1H-NMR (DMSO-D6) 8: 12.48 (1H, s), 11.93 (1H, s), 8.28 (1H, s), 7.88 (1H, d, J = 1.5 Hz), 7.63- 7.59 (2H, m), 7.47-7.44 (2H, m), 7.37 (1H, dd, J = 8.6, 1.9 Hz), 7.29 (1H, dd, J = 8.6, 1.9 Hz), 7.04 (2H, s) , 2.54 (3H, s).
- víXJv viXJv
- [5-am¡no-1-(2-metil- 1H-benc¡m¡dazol-5-¡l)- 1 Hpirazol-4-il] -(4- yodo-1 H-¡ ndol-2-il)- metanona 483 1H-RMN (DMSO-D6) 8: 12.23 (1 OH, s), 8.22 (1 .OH, s), 7.64-7.67 (2.0H, m), 7.54-7.48 (2.OH, m), 7.29 (1 .OH, dd, J = 8.3, 1.9 Hz), 7.10-6.95 (3.0H, m), 3.16 (2H, s), 2.53 (3H, s) [5-am-1-1 (2-methyl-1H-benzimdazol-5-l) - 1 Hpirazol-4-yl] - (4- iodine-1 H-ndol-2-yl ) - methanone 483 1 H-NMR (DMSO-D6) 8: 12.23 (1 OH, s), 8.22 (1 .OH, s), 7.64-7.67 (2.0H, m), 7.54-7.48 (2.OH, m ), 7.29 (1 .OH, dd, J = 8.3, 1.9 Hz), 7.10-6.95 (3.0H, m), 3.16 (2H, s), 2.53 (3H, s)
- í%¡r go
- 2-[5-amino-1-(2-metil- 1H-benc¡m¡dazol-5-¡l)- 1 Hpirazol-4-carbonil]- 1 H-indol-5-carbonitrilo 382 1H-RMN (DMSO-D6) 8: 12.46 (1 OH, s), 12.26 (1 .OH, s), 8.30-8.23 (2.0H, m), 7.60 (5.OH, m), 7.28 (1 .OH, d, J = 8.4 Hz), 7.05 (2.OH, m), 2.52 (3.0H, s)- 2- [5-Amino-1- (2-methyl- 1H-benzimdazol-5-l) - 1 Hpyrazol-4-carbonyl] - 1 H-indole-5-carbonitrile 382 1 H-NMR (DMSO -D6) 8: 12.46 (1 OH, s), 12.26 (1 .OH, s), 8.30-8.23 (2.0H, m), 7.60 (5.OH, m), 7.28 (1 .OH, d, J = 8.4 Hz), 7.05 (2.OH, m), 2.52 (3.0H, s) -
- [5-amlno-1-(2-metil- 1H-bendm¡dazol- 5-11)- 1 Hpirazol-4-il] -(6- bromo-5-fluoro-1H- ¡ndol-2-ll)-metanona 453,455 1H-RMN (DMSO-D6) 8: 12.16 (1.0H, s), 8.28 (1.0H, s), 7.73 (1.0H, m), 7.63-7.60 (3H. m), 7.44 (1.0H, s), 7.27 (1.0H, m), 7.05 (2.OH, br s), 2.53 (3H, s)- [5-amlno-1- (2-methyl- 1H-bendm¡dazol- 5-11) - 1 Hpirazol-4-yl] - (6- bromo-5-fluoro-1H- ndol-2-ll) - methanone 453,455 1H-NMR (DMSO-D6) 8: 12.16 (1.0H, s), 8.28 (1.0H, s), 7.73 (1.0H, m), 7.63-7.60 (3H. m), 7.44 (1.0H, s), 7.27 (1.0H, m), 7.05 (2.OH, br s), 2.53 (3H, s) -
1313
[5-amlno-1-(2-metll-1 H- bendmldazol-5-ll)-[5-amlno-1- (2-metll-1 H- bendmldazol-5-ll) -
1 Hplrazol-4-ll] -(5-etinil- 1 H-indol-2-il)-metanona1 Hplrazole-4-ll] - (5-ethynyl- 1 H-indol-2-yl) -methanone
381381
1H-RMN (DMSO-D6) 8: 12.45 (1.0H, s), 11.91 (1.0H, s), 8.29 (1.1H, s), 7.85 (1.0H, s), 7.61 (2.OH, m), 7.48 (2.0H, m), 7.34-7.28 (2.0H, m), 7.01-6.90 (2H, m), 3.99 (1.0H, s), 2.54 (3.0H, s).1 H-NMR (DMSO-D6) 8: 12.45 (1.0H, s), 11.91 (1.0H, s), 8.29 (1.1H, s), 7.85 (1.0H, s), 7.61 (2.OH, m) , 7.48 (2.0H, m), 7.34-7.28 (2.0H, m), 7.01-6.90 (2H, m), 3.99 (1.0H, s), 2.54 (3.0H, s).
1414
[5-amino-1-(2-metil-1 H- benclmldazol- 5-il)- 1 Hpirazol-4-il] -[6-(2-[5-amino-1- (2-methyl-1 H- benclmldazol-5-yl) - 1 Hpirazol-4-yl] - [6- (2-
fluorofenll)-1 H-indol-2- ¡Ij-metanonafluorofenll) -1 H-indole-2- Ij-methanone
451451
1H-RMN (DMSO-D6) 8: 8.35 (1H, s), 7.79 (1H, d, J = 8.6 Hz), 7.63-7.68 (6H, m), 7.62 (1H, s), 7.42-7.26 (3H, m), 7.05 (2H, br s), 2.54 (3H, s).1H-NMR (DMSO-D6) 8: 8.35 (1H, s), 7.79 (1H, d, J = 8.6 Hz), 7.63-7.68 (6H, m), 7.62 (1H, s), 7.42-7.26 (3H , m), 7.05 (2H, br s), 2.54 (3H, s).
[5-amino-1-(2-metll-1 H- bencimidazol- 5-II)- 1 Hplrazol-4-ll] -[6-(3-[5-amino-1- (2-metll-1 H- benzimidazol-5-II) - 1 Hplrazol-4-ll] - [6- (3-
fluorofenil)-1 H-lndol-2- ilj-metanonafluorophenyl) -1 H-lndol-2- ilj-methanone
451451
1H-RMN (DMSO-D6) 8: 12.48 (1H, s), 11.86 (1H, s), 8.34 (1H, s), 7.80 (1H, d, J = 8.6 Hz), 7.73 (2H, br s), 7.65-7.42 (25H, m), 7.30 (1H, d, J = 6.9 Hz), 7.02 (2H, br s), 2.54 (3H, s).1H-NMR (DMSO-D6) 8: 12.48 (1H, s), 11.86 (1H, s), 8.34 (1H, s), 7.80 (1H, d, J = 8.6 Hz), 7.73 (2H, br s) , 7.65-7.42 (25H, m), 7.30 (1H, d, J = 6.9 Hz), 7.02 (2H, br s), 2.54 (3H, s).
1616
[5-amlno-1-(2-metil-1 H- bencimidazol- 5-il)- 1 Hpirazol-4-il] -[6-(4-[5-amlno-1- (2-methyl-1 H- benzimidazol-5-yl) - 1 Hpirazol-4-yl] - [6- (4-
fluorofen¡l)-1 H-indol-2- ¡ll-metanonafluorophenol) -1 H-indole-2- ll-methanone
451451
1H-RMN (DMSO-D6) 8: 12.50 (1H, s), 11.82 (1H, s), 8.34 (1H, s), 7-81-7.65 (5H, m), 7.50 (1H, br s), 7.43-7.27 (5H, m), 7.03 (2H, brs), 2.54 (3H, s).1H-NMR (DMSO-D6) 8: 12.50 (1H, s), 11.82 (1H, s), 8.34 (1H, s), 7-81-7.65 (5H, m), 7.50 (1H, br s), 7.43-7.27 (5H, m), 7.03 (2H, brs), 2.54 (3H, s).
1717
1818
i-ii-i
OOR
r;r;
[5-amino-1-(2-met¡l-1 H- bendmidazol-5-il)- 1 Hpirazol-4-il -[6-(2- clorofenil)-1 H-indol-2-il]- 46g’ metanona[5-amino-1- (2-methyl-1 H- bendmidazol-5-yl) - 1 Hpirazol-4-yl - [6- (2- chlorophenyl) -1 H-indole-2-yl] - 46g 'methanone
1H-RMN (DMSO-D6) 8: 12.49 (1H, s), 11.84 (1H, s), 8.35 (1H, d, J = 3.1 Hz), 7.77 (1H, d, J = 8.2 Hz), 7.66 (1H, t, J = 4.2 Hz), 7.59-7.57 (3H, m), 7.53-7.50 (2H, brs), 7.49-7.39 (2H, m), 7.30 (1H, d, J = 6.8 Hz), 7.14 (1H, dd, J = 8.1, 1.3 Hz), 7.04 (2H, d, J = 14.5 Hz), 2.54 (3H, s).1H-NMR (DMSO-D6) 8: 12.49 (1H, s), 11.84 (1H, s), 8.35 (1H, d, J = 3.1 Hz), 7.77 (1H, d, J = 8.2 Hz), 7.66 ( 1H, t, J = 4.2 Hz), 7.59-7.57 (3H, m), 7.53-7.50 (2H, brs), 7.49-7.39 (2H, m), 7.30 (1H, d, J = 6.8 Hz), 7.14 (1H, dd, J = 8.1, 1.3 Hz), 7.04 (2H, d, J = 14.5 Hz), 2.54 (3H, s).
[5-am¡no-1-(1-metil-1H- bendmidazol-5-il)- 1 Hpirazol-4-il] -[6-(3- clorofenil)-1 H-indol-2-il]- 467, metanona 469[5-amine-1- (1-methyl-1 H- bendmidazol-5-yl) - 1 Hpirazol-4-yl] - [6- (3- chlorophenyl) -1 H-indole-2-yl] - 467, methanone 469
1H-RMN (DMSO-D6) 8: 12.49 (1H, s), 11.86 (1H, s), 8.34 (1H, d, J = 3.0 Hz), 7.80 (1H, d, J = 8.4 Hz), 7.12 (3H, m), 7.68-7.66 (3H, m), 7.63 (1H, d, J = 8.4 Hz), 7.61 (1H, d, J = 7.6 Hz), 7.43 (1H, d, J = 7.9 Hz), 7.30 (1H, ddd, J = 8.6, 4.1, 1.8 Hz), 7.05 (2H, d, J = 14.0 Hz), 2.54 (3H, s).1H-NMR (DMSO-D6) 8: 12.49 (1H, s), 11.86 (1H, s), 8.34 (1H, d, J = 3.0 Hz), 7.80 (1H, d, J = 8.4 Hz), 7.12 ( 3H, m), 7.68-7.66 (3H, m), 7.63 (1H, d, J = 8.4 Hz), 7.61 (1H, d, J = 7.6 Hz), 7.43 (1H, d, J = 7.9 Hz), 7.30 (1H, ddd, J = 8.6, 4.1, 1.8 Hz), 7.05 (2H, d, J = 14.0 Hz), 2.54 (3H, s).
[5-amino-1-(2-met¡l-1 H- bendmidazol-5-il)- 1 Hpirazol-4-il] -[6-(4- clorofenil)-1 H-indol-2-il]- 467, metanona 469[5-amino-1- (2-methyl-1 H- bendmidazol-5-yl) - 1 Hpirazol-4-yl] - [6- (4- chlorophenyl) -1 H-indole-2-yl] - 467, methanone 469
1H-RMN (DMSO-D6) 8: 12.49 (1H, s), 11.85 (1H, s), 8.34 (1H, s), 7.79 (2H, d, J = 8.1 Hz), 7.75-7.71 (2H, m), 7.72-7.68 (1H, m), 7.64-7.60 (1H, m), 7.54 (2H, d, J = 8.1 Hz), 7.51 (1H, d, J = 2.0 Hz), 7.41 (1H, dd, J=8.4, 1.6 Hz), 7.30 (1H, dd, J=8.7, 1.5 Hz), 7.05 (2H, br s), 2.54 (3H.1H-NMR (DMSO-D6) 8: 12.49 (1H, s), 11.85 (1H, s), 8.34 (1H, s), 7.79 (2H, d, J = 8.1 Hz), 7.75-7.71 (2H, m ), 7.72-7.68 (1H, m), 7.64-7.60 (1H, m), 7.54 (2H, d, J = 8.1 Hz), 7.51 (1H, d, J = 2.0 Hz), 7.41 (1H, dd, J = 8.4, 1.6 Hz), 7.30 (1H, dd, J = 8.7, 1.5 Hz), 7.05 (2H, br s), 2.54 (3H.
s).s).
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 20 twenty
- H [5-amino-1-(2-met¡l-1H- bencimidazol-5-il)- 1 Hpirazol-4-il] -[6-(2- trifluorometil-fenil)-1 H- ¡ndol-2-¡l]-metanona 501 1H-RMN (CD30D) 8: 8.32 (1H, s), 7.96 (1H, s), 7.85 (1H, d, J = 8.7 Hz), 7.77 (1H, t, J = 8.6 Hz), 7.68- 7.52 (5H, m), 7.42 (1H, dt, 3 = 13.3, 5.4 Hz), 7.06 (2H, d, J = 8.7 Hz), 2.65 (3H, s). H [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1 Hpirazol-4-yl] - [6- (2- trifluoromethyl-phenyl) -1 H- ndol-2 -¡L] -methanone 501 1H-NMR (CD30D) 8: 8.32 (1H, s), 7.96 (1H, s), 7.85 (1H, d, J = 8.7 Hz), 7.77 (1H, t, J = 8.6 Hz), 7.68- 7.52 (5H, m), 7.42 (1H, dt, 3 = 13.3, 5.4 Hz), 7.06 (2H, d, J = 8.7 Hz), 2.65 (3H, s).
- 21 twenty-one
- [5-amino-1-(2-met¡l-1H- bencimidazol-5-il)- 1 Hpi razol-4-il] -[6-(3- trifluorometil-fenil)-1 H- ¡ndol-2-¡l]-metanona 501 1H-RMN (CD30D) 8: 8.29 (11H, s), 7.94 (2H, br s), 7.83 (1H, dd, J = 8.4, 0.7 Hz), 7.76-7.75 (1H, m), 7.67 (1H, brs), 7.65-7.62 (2H, m), 7.43 (1H, d, J = 1.5 Hz), 7.40-7.39 (2H, m), 7.36 (1H, d, J = 2.0 Hz), 2.61 (3H, s), [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) - 1 Hpi razol-4-yl] - [6- (3- trifluoromethyl-phenyl) -1 H- ndol-2 -¡L] -methanone 501 1H-NMR (CD30D) 8: 8.29 (11H, s), 7.94 (2H, br s), 7.83 (1H, dd, J = 8.4, 0.7 Hz), 7.76-7.75 (1H, m), 7.67 (1H, brs), 7.65-7.62 (2H, m), 7.43 (1H, d, J = 1.5 Hz), 7.40-7.39 (2H, m), 7.36 (1H, d, J = 2.0 Hz ), 2.61 (3H, s),
- 22 22
- ’*lCScri-L^ s^-Oír H [5-amino-1-(2-met¡l-1H- bencimidazol-5-il)- 1 Hpirazol-4-il] -[6-(4- trifluorometil-fenil)-1 H- ¡ndol-2-¡l]-metanona 501 1H-RMN (CD30D) 8: 8.31 (1H, s), 7.89 (2H, d, J = 8.1 Hz), 7.85 (1H, dd, J = 8.3, 0.7 Hz), 7.81-7.80 (1H, m), 7.75 (2H. d, J = 8.1 Hz), 7.69- 7.65 (2H, m), 7.46 (1H, dd, J = 8.4, 1.6 Hz), 7.43 (2H, d, J = 0.8 Hz), 7.39 (2H, dd, J = 8.5, 2.1 Hz), 2.62 (3H, s). '* lCScri-L ^ s ^ -Hear H [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) - 1 Hpirazol-4-yl] - [6- (4- trifluoromethyl- phenyl) -1 H- ¡ndol-2-¡l] -methanone 501 1H-NMR (CD30D) 8: 8.31 (1H, s), 7.89 (2H, d, J = 8.1 Hz), 7.85 (1H, dd, J = 8.3, 0.7 Hz), 7.81-7.80 (1H, m), 7.75 (2H. D, J = 8.1 Hz), 7.69- 7.65 (2H, m), 7.46 (1H, dd, J = 8.4, 1.6 Hz ), 7.43 (2H, d, J = 0.8 Hz), 7.39 (2H, dd, J = 8.5, 2.1 Hz), 2.62 (3H, s).
- 23 2. 3
- - [5-am¡ no-1 -(2-metil-1 H- benclmldazol-5-il)- 1 Hpirazol-4-il] -(4- bromo-1 H-indol-2-il)- metanona 435,437 1H-RMN (DMSO-D6) 8: 13.0-11.5 (1H, s), 11.2-10.5 (1H, s), 8.28 (1H, s), 7.60 (2H, t, J = 4.3 Hz), 7.49 (1H, d, J = 8.4 Hz), 7.29-7.25 (2H, m), 7.14 (2H, t, J = 9.1 Hz), 3.17 (2H, s), 2.53 (3H, s). - [5-am¡ no-1 - (2-methyl-1 H- benclmldazol-5-yl) - 1 Hpirazol-4-yl] - (4- bromo-1 H-indole-2-yl) - methanone 435,437 1H-NMR (DMSO-D6) 8: 13.0-11.5 (1H, s), 11.2-10.5 (1H, s), 8.28 (1H, s), 7.60 (2H, t, J = 4.3 Hz), 7.49 (1H , d, J = 8.4 Hz), 7.29-7.25 (2H, m), 7.14 (2H, t, J = 9.1 Hz), 3.17 (2H, s), 2.53 (3H, s).
- 24 24
- <XOHr- vtO^' [5-amino-1-(2-metil-1H- bendmidazol-5-il)- 1 Hpirazol-4-il] -[6-(3- fluoropiridin-2-¡l)-1H- ¡ndol -2-il]-metanona 452 1H-RMN (DMSO-D6) 8: 12.49 (1H, s), 11.94 (1H, d, J = 2.2 Hz), 8.57 (1H, td, J = 3.0, 1.5 Hz), 8.36 (1H, s), 8.13 (1H, s), 7.87-7.81 (2H, m), 7.73 (1H, dt, J =8.6, 1.6 Hz), 7.64- 7.62 (2H, m), 7.52 (1H, d, J = 1.5 Hz), 7.49-7.45 (1H, m), 7.31 (1H, dd, J = 8.6, 1.9 Hz), 7.06 (2H, s), 2.54 (3H, s). <XOHr- vtO ^ '[5-amino-1- (2-methyl-1H- bendmidazol-5-yl) - 1 Hpyrazol-4-yl] - [6- (3- fluoropyridin-2-l) -1H - ndol -2-yl] -methanone 452 1H-NMR (DMSO-D6) 8: 12.49 (1H, s), 11.94 (1H, d, J = 2.2 Hz), 8.57 (1H, td, J = 3.0, 1.5 Hz), 8.36 (1H, s), 8.13 (1H, s), 7.87-7.81 (2H, m), 7.73 (1H, dt, J = 8.6, 1.6 Hz), 7.64- 7.62 (2H, m), 7.52 (1H, d, J = 1.5 Hz), 7.49-7.45 (1H, m), 7.31 (1H, dd, J = 8.6, 1.9 Hz), 7.06 (2H, s), 2.54 (3H, s).
- 25 25
- [5-amino-1-(2-met¡l-1H- bencimidazol-5-il)- 1 Hpirazol-4-il] -(6-metil- 1 H-¡ndol-2-¡l)-metanona 371 1H-RMN (DMSO-D6) 8: 12.44 (1.0H, d, J = 3.7 Hz), 11.63 (1.0H, d, J = 1.6 Hz), 8.28 (1.0H, d, J = 4.7 Hz), 7.67-7.62 (1.0H, m), 7.59-7.54 (2.OH, m), 7.39 (1.1H, s), 7.32-7.24 (2.OH, m), 7.03-6.84 (3.0H, m), 2.53 (3.OH, s), 2.41 (3.OH, s). [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 Hpirazol-4-yl] - (6-methyl- 1 H-landol-2-l) -methanone 371 1 H-NMR (DMSO-D6) 8: 12.44 (1.0H, d, J = 3.7 Hz), 11.63 (1.0H, d, J = 1.6 Hz), 8.28 (1.0H, d, J = 4.7 Hz), 7.67 -7.62 (1.0H, m), 7.59-7.54 (2.OH, m), 7.39 (1.1H, s), 7.32-7.24 (2.OH, m), 7.03-6.84 (3.0H, m), 2.53 (3.OH, s), 2.41 (3.OH, s).
- 26 26
- * <s*o^- [5-ami no-1 -(2-met¡l-1 H- bencimidazol-5-il)- IHpirazol- 4-¡l] -[5-(4,4- difluoro-piperidina-1- carbonil)-1 H-indol-2-il]- metanona 504 1H-RMN (DMSO-D6) 8: 12.42 (1.0H, s), 11.88 (1.0H, s), 8.28 (1.0H, s), 7.80 (1.0H, d, J = 1.2 Hz), 7.65-7.45 (4.OH, m), 7.32 (1.0H, dd, J = 8.4, 1.6 Hz), 7.26 (1.0H, m), 7.05-6.90 (2.OH, m), 3.70-3.55 (4.OH, m), 2.51 (3H, s), 2.10-1.95 (4.OH, m). * <s * o ^ - [5-ami no-1 - (2-meti-1 H- benzimidazol-5-yl) - I-pyrazol-4-yl] - [5- (4,4- difluoro- piperidine-1- carbonyl) -1 H-indol-2-yl] - methanone 504 1H-NMR (DMSO-D6) 8: 12.42 (1.0H, s), 11.88 (1.0H, s), 8.28 (1.0H, s), 7.80 (1.0H, d, J = 1.2 Hz), 7.65-7.45 (4.OH, m), 7.32 (1.0H, dd, J = 8.4, 1.6 Hz), 7.26 (1.0H, m), 7.05-6.90 (2.OH, m), 3.70-3.55 (4.OH, m), 2.51 (3H, s), 2.10-1.95 (4.OH, m).
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 27 27
- ■f. [5-amino-1-(2-metil-1 H- bencimidazol-5-il)- 1 Hpirazol-4-il] -[5-(3,3- difluoro-pi peridi na-1- carbonil)-1 H-indol-2-il]- metanona 504 1H-RMN (DMSO-D6) 8: 12.42 (1.0H, s), 11.90 (1.0H, s), 8.28 (1.0H, s), 7.74 (1..0H, d, J = 0.8 Hz), 7.65-7.45 (4.0H, m), 7.30-7.23 (2.0H, m), 6.99 (2.0H, m), 3.84 (2.0H, m), 3.51 (2.0H, m), 2.51 (3.0H, s), 2.20-2.00 (2.0, m), 1.74-1.60 (2.0H, s). ■ f. [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 Hpirazol-4-yl] - [5- (3,3-difluoro-pi peridi na-1- carbonyl) -1 H-indole-2-yl] - methanone 504 1H-NMR (DMSO-D6) 8: 12.42 (1.0H, s), 11.90 (1.0H, s), 8.28 (1.0H, s), 7.74 (1 .. 0H, d, J = 0.8 Hz), 7.65-7.45 (4.0H, m), 7.30-7.23 (2.0H, m), 6.99 (2.0H, m), 3.84 (2.0H, m), 3.51 (2.0H , m), 2.51 (3.0H, s), 2.20-2.00 (2.0, m), 1.74-1.60 (2.0H, s).
- 28 28
- H ■ . a i*, (2,2,2-trifluoroetil)-amida del ácido 2-[5-amino-1- (2-metil-1H- bencimidazol-5-il)-1 H- pirazol- 4-carbonil]-1H- indol-5-carboxílico 482 1H-RMN (DMSO-D6) 8: 12.43 (1.0H, s), 11.96 (1.0H, s), 8.98 (1.0H, d, J = 6.5 Hz), 8.31 (2.0H, m), 7.79 (1.0H, dd, J = 8.7, 1.7 Hz), 7.70-7.50 (4.0H, m), 7.28 (1.0H, m), 7.05-6.90 (2.0H, m), 4.154.00 (2.0H, m), 2.52 (3.0H, s). H ■. 2- [5-Amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 H- pyrazol-4-carbonyl] -1H ai *, (2,2,2-trifluoroethyl) -amide - indole-5-carboxylic 482 1H-NMR (DMSO-D6) 8: 12.43 (1.0H, s), 11.96 (1.0H, s), 8.98 (1.0H, d, J = 6.5 Hz), 8.31 (2.0H , m), 7.79 (1.0H, dd, J = 8.7, 1.7 Hz), 7.70-7.50 (4.0H, m), 7.28 (1.0H, m), 7.05-6.90 (2.0H, m), 4.154.00 (2.0H, m), 2.52 (3.0H, s).
- 29 29
- v-vy Ih [5-amino-1-(2-metil-1 H- bencimidazol- 5-il)- 1Hpirazol- 4-il] -[6-(5- trifluorometil-piridin-2-il)- 1 H-indol-2-il]-metanona 502 1H-RMN (DMSO-D6) 8: 12.49 (1H, s), 12.02 (1H, d, J = 1.6 Hz), 9.06 (1H, d, J = 1.1 Hz), 8.35 (2H, s), 8.28 (1H, dd, J = 8.8, 2.2 Hz), 8.21 (1H, d, J = 8.2 Hz), 7.91 (1H, dd, J = 8.2, 1.6 Hz), 7.84 (1H, d, J = 8.2 Hz), 7.64-7.62 (2H, m), 7.53 (1H, d, J = 1.1 Hz), 7.31 (1H, dd, J = 8.2, 2.2 Hz), 7.07 (2H, s), 2.54 (3H, s). v-v and Ih [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1Hpirazol-4-yl] - [6- (5- trifluoromethyl-pyridin-2-yl) - 1 H -indole-2-yl] -methanone 502 1H-NMR (DMSO-D6) 8: 12.49 (1H, s), 12.02 (1H, d, J = 1.6 Hz), 9.06 (1H, d, J = 1.1 Hz) , 8.35 (2H, s), 8.28 (1H, dd, J = 8.8, 2.2 Hz), 8.21 (1H, d, J = 8.2 Hz), 7.91 (1H, dd, J = 8.2, 1.6 Hz), 7.84 ( 1H, d, J = 8.2 Hz), 7.64-7.62 (2H, m), 7.53 (1H, d, J = 1.1 Hz), 7.31 (1H, dd, J = 8.2, 2.2 Hz), 7.07 (2H, s ), 2.54 (3H, s).
- 30 30
- ‘11 -n^iT1 pS?: Ó*’ -■ [5-amino-1-(2-metil-1 H- bencimidazol-5-il)- 1 Hpirazol-4-il] -[6-(6- trifluorometil-piridin-2-il)- 1 H-indol-2-il]-metanona 502 1H-RMN (DMSO-D6) 8: 12.48 (1H, s). 11.94 (1H, d, J = 2.2 Hz), 8.34-8.31 (3H, m), 8.16 (1H, t, J = 7.7 Hz), 7.887.84 (3H, m), 7.65-7.58 (2H, m), 7.52 (1H, d, J = 1.6 Hz), 7.31-7.30 (1H, m), 7.06 (2H, d, J = 22.0 Hz), 2.64 (3H, s). '11 -n ^ iT1 pS ?: Ó * '- ■ [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) - 1 Hpirazol-4-yl] - [6- (6- trifluoromethyl-pyridin-2-yl) -1 H-indol-2-yl] -methanone 502 1 H-NMR (DMSO-D6) 8: 12.48 (1H, s). 11.94 (1H, d, J = 2.2 Hz), 8.34-8.31 (3H, m), 8.16 (1H, t, J = 7.7 Hz), 7,887.84 (3H, m), 7.65-7.58 (2H, m) , 7.52 (1H, d, J = 1.6 Hz), 7.31-7.30 (1H, m), 7.06 (2H, d, J = 22.0 Hz), 2.64 (3H, s).
- 31 31
- i N ^ >- *■ [5-amino-1-(2-metil-1 H)- bencimidazol-5-il)-1 H- pirazol-4-il] -[6-(5-cloro- piridin-2-il)-1 H-indol-2-il]- metanona 468, 470 1H-RMN (DMSO-D6) 8: 12.48 (1H, s), 11.95 (1H, s), 8.72 (1H, dd, J = 2.2, 1.1 Hz), 8.34 (1H, s), 8.25 (1H, s), 8.047.99 (2H, m), 7.82-7.80 (2H,m), 7.63 (2H, s), 7.51 (1H, s), 7.30 (1H, dd, J = 8.5, 1.9 Hz), 7.05 (2H, d, J = 6.6 Hz), 2.54 (3H, s). i N ^> - * ■ [5-amino-1- (2-methyl-1 H) - benzimidazol-5-yl) -1 H- pyrazol-4-yl] - [6- (5-chloro-pyridin- 2-yl) -1 H-indol-2-yl] - methanone 468, 470 1H-NMR (DMSO-D6) 8: 12.48 (1H, s), 11.95 (1H, s), 8.72 (1H, dd, J = 2.2, 1.1 Hz), 8.34 (1H, s), 8.25 (1H, s), 8.047.99 (2H, m), 7.82-7.80 (2H, m), 7.63 (2H, s), 7.51 (1H, s), 7.30 (1H, dd, J = 8.5, 1.9 Hz), 7.05 (2H, d, J = 6.6 Hz), 2.54 (3H, s).
- 32 32
- ¿Va* 1 1 J—í w [5-amino-1-(2-metil-1 H- bencimidazol-5-il)- 1 Hpirazol-4-il] -[6-(4- metilpiridin-1-il)-1H-indol -2-il] metanona 448 1H-RMN (CD3OD) 8: 8.46 (1H, dd, J = 5.2, 0.4 Hz), 8.31 (1H, s), 8.05-8.04 (1H, m), 7.93 (1H, dd, J=8.0,1.7 Hz), 7.84 (1H, dd, J = 8.4, 0.1 Hz), 7.77-7.76 (1H, m), 7.69-7.67 (2H, m), 7.43 (1H, d, J = 0.8 Hz), 7.39 (1H, dd, J = 8.6, 2.0 Hz), 7.22-7.13 (1H, m), 2.62 (3H, s), 2.48 (3H, s). Does * 1 1 J — í w [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) - 1 Hpirazol-4-yl] - [6- (4- methylpyridin-1-yl) ) -1H-indole -2-yl] methanone 448 1H-NMR (CD3OD) 8: 8.46 (1H, dd, J = 5.2, 0.4 Hz), 8.31 (1H, s), 8.05-8.04 (1H, m), 7.93 (1H, dd, J = 8.0.1.7 Hz), 7.84 (1H, dd, J = 8.4, 0.1 Hz), 7.77-7.76 (1H, m), 7.69-7.67 (2H, m), 7.43 (1H, d, J = 0.8 Hz), 7.39 (1H, dd, J = 8.6, 2.0 Hz), 7.22-7.13 (1H, m), 2.62 (3H, s), 2.48 (3H, s).
- 33 33
- o;ClTCd-L»-. [5-amino-1-(2-metil-1 H- bencimidazol-5-il)- 1 Hpirazol-4-il] -[6-(3- cloro-4-fluoro-fenil)-1 H- indol-2-il]-metanona 484, 486 1H-RMN (DMSO-D6) 8: 12.48 (1H, s), 11.85 (1H, s), 8.34 (1H, s), 7.87 (1 H, dd, J = 7.1, 2.2 Hz), 7.79 (1H, d, J = 8.2 Hz), 7.74-7.66 (2H, m), 7.65-7.58 (2H, m), 7.57-7.49 (2H, m), 7.41 (1H, d, J = 8.2 Hz), 7.30 (1H, d, J = 8.2 Hz), 7.04 (2H, s), 2.54 (3H, s). or; ClTCd-L »-. [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 Hpirazol-4-yl] - [6- (3- chloro-4-fluoro-phenyl) -1 H- indole- 2-yl] -methanone 484, 486 1H-NMR (DMSO-D6) 8: 12.48 (1H, s), 11.85 (1H, s), 8.34 (1H, s), 7.87 (1 H, dd, J = 7.1 , 2.2 Hz), 7.79 (1H, d, J = 8.2 Hz), 7.74-7.66 (2H, m), 7.65-7.58 (2H, m), 7.57-7.49 (2H, m), 7.41 (1H, d, J = 8.2 Hz), 7.30 (1H, d, J = 8.2 Hz), 7.04 (2H, s), 2.54 (3H, s).
- Ejemplo Example
- Estructura Nombre del compuesto miz 1H-RMN Structure Name of compound miz 1H-NMR
- 34 3. 4
- [5-amino-1-(2-metil-1 H- bencimidazol-5-il)- 1 Hpirazol-4-il] -[6-(3- trifluorometil-piridin-2-il)- 1 H-indol-2-il]-metanona 502 1H-RMN (DMSO-D6) 8: 12.48 (1H, s), 11.96 (1H, s), 8.95 (1H, d, J = 4.9 Hz), 8.35-8.34 (2H, m), 8.26 (1H, s), 7.93 (1H, dd, J = 8.5, 1.4 Hz), 7.82 (1H, d, J = 8.2 Hz), 7.70 (1H, d, J = 5.5 Hz), 7.62-7.60 (2H, m), 7.52 (1H, s), 7.30 (1H, dd, J = 6.5, 1.9 Hz), 7.06 (2H, s), 2.54 (3H, s). [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 Hpirazol-4-yl] - [6- (3- trifluoromethyl-pyridin-2-yl) - 1 H-indole- 2-yl] -methanone 502 1H-NMR (DMSO-D6) 8: 12.48 (1H, s), 11.96 (1H, s), 8.95 (1H, d, J = 4.9 Hz), 8.35-8.34 (2H, m ), 8.26 (1H, s), 7.93 (1H, dd, J = 8.5, 1.4 Hz), 7.82 (1H, d, J = 8.2 Hz), 7.70 (1H, d, J = 5.5 Hz), 7.62-7.60 (2H, m), 7.52 (1H, s), 7.30 (1H, dd, J = 6.5, 1.9 Hz), 7.06 (2H, s), 2.54 (3H, s).
- 35 35
- ^"CXr [5-amino-1-(2-metil-1 H- bencimidazol-5-il)- 1 Hpirazol-4-il] -[6-(4- trifluorometil-piridin-2-il)- 1 H-indol-2-il] metanona 502 1H-RMN (DMSO-D6) 8: 12.47 (1H, s), 11.90 (1H, d, J = 1.6 Hz), 8.92 (1H, d, J = 3.8 Hz), 8.35-8.31 (2H, m), 7.78 (1H, d. J = 8.2 Hz), 7.67-7.60 (4H, m), 7.53 (1H, d. J = 1.6 Hz), 7.30 (1H, d, J = 8.2 Hz), 7.19 (1H, d, J = 8.2 Hz), 7.04 (2H, d, J = 10.4 Hz), 2.54 (3H, s). ^ "CXr [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 Hpirazol-4-yl] - [6- (4- trifluoromethyl-pyridin-2-yl) - 1 H -indole-2-yl] methanone 502 1H-NMR (DMSO-D6) 8: 12.47 (1H, s), 11.90 (1H, d, J = 1.6 Hz), 8.92 (1H, d, J = 3.8 Hz), 8.35-8.31 (2H, m), 7.78 (1H, d. J = 8.2 Hz), 7.67-7.60 (4H, m), 7.53 (1H, d. J = 1.6 Hz), 7.30 (1H, d, J = 8.2 Hz), 7.19 (1H, d, J = 8.2 Hz), 7.04 (2H, d, J = 10.4 Hz), 2.54 (3H, s).
[Ejemplo 36: Síntesis de la [5-amino-1 -(6-fluoro-2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-¡l]-(1 H-¡ndol-2-M)- metanona][Example 36: Synthesis of [5-amino-1 - (6-fluoro-2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-l] - (1 H-landol -2-M) - methanone]
5 La [5-am¡no-1-(6-fluoro-2-metil-1H-benc¡midazol-5-¡l)-1H-p¡razol-4-¡l]-(1-bencenosulfonil-1H-¡ndol-2-¡l) metanona (114 mg, 0.22 mmol) se disolvió en ¡sopropanol (2.2 mi), y se le adicionó una solución acuosa de hidróxido de sodio 1 M (2.2 mi). La mezcla resultante se calentó a 90°C con agitación bajo una atmósfera de nitrógeno, durante dos horas. Después la mezcla de reacción se enfrió a temperatura ambiente, se le adicionaron agua y una solución acuosa saturada de dihidrógenofosfato de sodio. El producto se extrajo con acetato de etilo. La capa orgánica se aisló, se5 [5-Amno-1- (6-fluoro-2-methyl-1H-benzylmidazol-5-l) -1H-p¡razol-4-l] - (1-benzenesulfonyl-1H -¡Ndol-2-¡l) methanone (114 mg, 0.22 mmol) was dissolved in sopropanol (2.2 ml), and a 1 M aqueous solution of sodium hydroxide (2.2 ml) was added. The resulting mixture was heated at 90 ° C with stirring under a nitrogen atmosphere, for two hours. After the reaction mixture was cooled to room temperature, water and a saturated aqueous solution of sodium dihydrogen phosphate were added. The product was extracted with ethyl acetate. The organic layer was isolated,
10 lavó con una solución acuosa saturada de cloruro de sodio, y se secó sobre sulfato de magnesio. El desecante se eliminó por filtración. El filtrado se concentró bajo presión reducida, y el residuo resultante se purificó por cromatografía de columna de sílica gel (sílica gel amino; diclorometano/metanol = 100/5) para dar la [5-amino-1-(6- fluoro-2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(1H-indol-2-il) metanona como un sólido de color amarillo (75 mg, 89.8%).10 washed with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (silica gel amino; dichloromethane / methanol = 100/5) to give the [5-amino-1- (6- fluoro-2 -methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (1H-indole-2-yl) methanone as a yellow solid (75 mg, 89.8%).
15 1H-NNM (DMSO-De) 8: 12.60 (1.0H, brs), 11.70 (1.0H, brs), 8.31 (1.0H, s), 7.69 (1.0H, d, J = 7.6 Hz), 7.62 (1.0H, d, J = 6.8 Hz), 7.55 (1 .OH, d, J = 10.7 Hz), 7.50-7.45 (2.0H, m), 7.25 (1.0H, dd, J = 7.6, 7.6 Hz), 7.08 (1.0H, dd, J = 7.6,15 1H-NNM (DMSO-De) 8: 12.60 (1.0H, brs), 11.70 (1.0H, brs), 8.31 (1.0H, s), 7.69 (1.0H, d, J = 7.6 Hz), 7.62 ( 1.0H, d, J = 6.8 Hz), 7.55 (1 .OH, d, J = 10.7 Hz), 7.50-7.45 (2.0H, m), 7.25 (1.0H, dd, J = 7.6, 7.6 Hz), 7.08 (1.0H, dd, J = 7.6,
7.6 Hz), 7.02 (2.OH, brs), 2.53 (3.0H, s) ESI (LC-MS modo positivo) m/z 375 [(M+H)+j7.6 Hz), 7.02 (2.OH, brs), 2.53 (3.0H, s) ESI (LC-MS positive mode) m / z 375 [(M + H) + j
Los compuestos de los Ejemplos 37 a 63 enumerados en la Tabla 2, se sintetizaron mediante el mismo método como en el Ejemplo 36.The compounds of Examples 37 to 63 listed in Table 2, were synthesized by the same method as in Example 36.
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 37 37
- V’-0-V ácido 2-[8-amino-(2- metil-IH- bencimidazol-5-il)-1 H- pirazol-4-carbonol]- 1 H-indol-6-carboxílico 401 1H-RMN (DMSO-D6) 8:12.74 (1H, br s),12.06 (1H, s), 8.36 (1H s), 8.16 (1H, s), 7.78-7.76(3H, m), 7.66 (1H, dd, J =8.4, 1.4 Hz), 7.52 (1H, dd, J = 2.2, 0.8 Hz), 7.49 (1H, brs), 7.17 (2H, br s). 2.67 (3H, s). V'-0-V 2- [8-amino- (2- methyl-IH-benzimidazol-5-yl) -1 H- pyrazol-4-carbonol] - 1 H-indole-6-carboxylic acid 401 1 H-NMR (DMSO-D6) 8: 12.74 (1H, br s), 12.06 (1H, s), 8.36 (1H s), 8.16 (1H, s), 7.78-7.76 (3H, m), 7.66 (1H, dd, J = 8.4, 1.4 Hz), 7.52 (1H, dd, J = 2.2, 0.8 Hz), 7.49 (1H, brs), 7.17 (2H, br s). 2.67 (3H, s).
- 38 38
- H [5-amino-1-(2-met¡l- 1H-bencimidazol-5-il)- 1 H-p¡razol-4-il] -(6- hidroximetil-1 H-indol- 2-il)-metanona 387 1 H-RMN(CD30D) 8: 8.32 (1H, s), 7.89(1 H,d, J = 2.2 Hz), 7.66 (1H, d, J =8.8 Hz). 7.70-7.69 (2H, m), 7.49 (1H, s), 7.36 (1H, s), 7.11(1 H, dd, J=8.2, 1.1 Hz), 4.72 (2H, s), 2.83 (3H, s), H [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) - 1 Hp¡razol-4-yl] - (6- hydroxymethyl-1 H-indole-2-yl) -methanone 387 1 H-NMR (CD30D) 8: 8.32 (1H, s), 7.89 (1 H, d, J = 2.2 Hz), 7.66 (1H, d, J = 8.8 Hz). 7.70-7.69 (2H, m), 7.49 (1H, s), 7.36 (1H, s), 7.11 (1 H, dd, J = 8.2, 1.1 Hz), 4.72 (2H, s), 2.83 (3H, s ),
- 39 39
- ,0~'OJ Or [5-amino-1-(2-metil- 1 H-bencimidazol-5-il)- 1 H-pirazol-4-il]-{6-[2- (4-metil-piperazin-1- il)-etoxi]-1 H-indol-2-il}- metanona 499 1 H-RMN(DMSO-D6) 8: 12.51(1.OH, brs), (1 .OH, brs), 8.27 (10H, s), 7.61-7.55 (3.0H, m), 7.40 (1 OH, br s), 7.29 (10H, dd, J = 8.3, 2.0 Hz), 6.94-6.93 (3.0H, m), 6.74 (1 .OH, dd, J = 8.8, 2.0 Hz). 4.03 (2.0H, t, J = 5.8 Hz), 3.32-3.30 (4.0H, m), 2.72 (2.0H, t, J = 5.8 Hz), 2.53 (3.OH, s), 2.34-2.32 (4.OH, brm), 2.15 (3.0H. s). , 0 ~ 'OJ Or [5-amino-1- (2-methyl- 1 H -benzimidazol-5-yl) - 1 H -pyrazol-4-yl] - {6- [2- (4-methyl-piperazin -1-yl) -ethoxy] -1 H-indol-2-yl} - methanone 499 1 H-NMR (DMSO-D6) 8: 12.51 (1.OH, brs), (1 .OH, brs), 8.27 (10H, s), 7.61-7.55 (3.0H, m), 7.40 (1 OH, br s), 7.29 (10H, dd, J = 8.3, 2.0 Hz), 6.94-6.93 (3.0H, m), 6.74 (1 .OH, dd, J = 8.8, 2.0 Hz). 4.03 (2.0H, t, J = 5.8 Hz), 3.32-3.30 (4.0H, m), 2.72 (2.0H, t, J = 5.8 Hz), 2.53 (3.OH, s), 2.34-2.32 (4 .OH, brm), 2.15 (3.0H. S).
- 40 40
- SuO^Lr ”"G> [5-amino-1-(2-metil- 1 H-bencimidazol-5-il)- 1 H-pirazol-4-il] -[6-(3- metil-oxetan-3- ilmetoxi)-1 H-indol-2- ilj-metanona 457 1 H-RMN(DMSO-D6) 8:12.54(1.0H, br s), 11.55(1 OH, br s), 8.28 (1.0H, s), 7.61-7.57 (3.OH. m), 7.41 (1.0H, br s), 7.28 (1.0H, dd, J = 8.3. 2.0 Hz), 697-6.95 (3.0H, m), 6.79 (1 .OH, dd, J = 8.8, 2.4 Hz), 4.55 (2.OH, d, J = 5.9 Hz), 4.33. (2.0H, d, J = 5.9 Hz), 4.08 (2.OH, s), 2.53 (3.0H, s), 1.40 (3.OH, s). SuO ^ Lr "" G> [5-amino-1- (2-methyl- 1 H -benzimidazol-5-yl) - 1 H -pyrazol-4-yl] - [6- (3- methyl-oxetan-3 - ilmethoxy) -1 H-indol-2- ilj-methanone 457 1 H-NMR (DMSO-D6) 8: 12.54 (1.0H, br s), 11.55 (1 OH, br s), 8.28 (1.0H, s ), 7.61-7.57 (3.OH.m), 7.41 (1.0H, br s), 7.28 (1.0H, dd, J = 8.3. 2.0 Hz), 697-6.95 (3.0H, m), 6.79 (1 .OH, dd, J = 8.8, 2.4 Hz), 4.55 (2.OH, d, J = 5.9 Hz), 4.33. (2.0H, d, J = 5.9 Hz), 4.08 (2.OH, s), 2.53 (3.0H, s), 1.40 (3.OH, s).
- 41 41
- OXrKr r c"O0- H [5-amlno-1-(2-met¡l- 1 H-benclmldazol-5-ll)- 1 H-plrazol-4-il] -[6-(3- fluoro-piperldln-1- ilmetil)-1 H-indol-2-ll]- metanona 472 1H-RMN (DMSO-D6) 8: 12.48 (1.0H, br s), 11.65 (1.0H, br s), 8.30 (1.0H, s), 7.64- 7.62 (3.OH, m), 7.43 (1.0H, br s), 7.40 (1.0H, br s), 7.29 (1.0H, dd, J = 8.3,10 Hz), 7.04-7.02 (3.OH, m), 4.69-4.57 (1.0H, m), 3.59 (2.OH, s), 2.74-2.67 (1 OH, m), 2.53 (3.OH, s), 2.51-2.49 (1.0H, m), 2.46- 2.33 (1.0H, m), 2.28-2.23 (1.0H, m), (2.0H, m), 1.55-1.43 (2.OH, m). OXrKr rc "O0- H [5-amlno-1- (2-methyl-1 H-benclmldazol-5-ll) - 1 H-plrazol-4-yl] - [6- (3- fluoro-piperldln- 1- ilmethyl) -1 H-indole-2-ll] - methanone 472 1 H-NMR (DMSO-D6) 8: 12.48 (1.0H, br s), 11.65 (1.0H, br s), 8.30 (1.0H, s), 7.64- 7.62 (3.OH, m), 7.43 (1.0H, br s), 7.40 (1.0H, br s), 7.29 (1.0H, dd, J = 8.3.10 Hz), 7.04-7.02 (3.OH, m), 4.69-4.57 (1.0H, m), 3.59 (2.OH, s), 2.74-2.67 (1 OH, m), 2.53 (3.OH, s), 2.51-2.49 ( 1.0H, m), 2.46-2.33 (1.0H, m), 2.28-2.23 (1.0H, m), (2.0H, m), 1.55-1.43 (2.OH, m).
- 42 42
- *rc¿H-<~ ^ “*XJV w [5-amlno-1-(2-metll- 1H-benc¡m¡dazol- 5- ¡l)-1 H-pirazol-4-il] -(6- {[bis(2-metoxletll)- amino]-metll}-1H- indol-2-ll)-metanona 502 1H-RMN (DMSO-D6) 8: 12.49 (1.0H, br s). 11.62 (1 .OH, br s), 8.30 (1.0H, s), 7.62- 7.60 (3.OH, m), 7.410 (1.0H, br s), 7.41 (1.0H, brs), 7.29 (1.0H, d, J= 8.3 Hz), 7.05 (1.0H, d, J =7.8 Hz), 6.99 (1.0H, br s), 6.97 (1 .OH, br s), 3.73 (2.0H, s), 3.42 (4.OH, t, J = 6.1 Hz), 3.22 (3.0H, s), 3.22 (3.OH, 9), 2.66 (4.OH, t, J = 6.1 Hz), 2.53 (3.OH, s). * rc¿H- <~ ^ “* XJV w [5-amlno-1- (2-metll- 1H-benc¡m¡dazol- 5- ¡l) -1 H-pyrazole-4-yl] - (6 - {[bis (2-methoxletll) -amino] -metll} -1H- indole-2-ll) -methanone 502 1H-NMR (DMSO-D6) 8: 12.49 (1.0H, br s). 11.62 (1 .OH, br s), 8.30 (1.0H, s), 7.62-7.60 (3.OH, m), 7.410 (1.0H, br s), 7.41 (1.0H, brs), 7.29 (1.0H , d, J = 8.3 Hz), 7.05 (1.0H, d, J = 7.8 Hz), 6.99 (1.0H, br s), 6.97 (1 .OH, br s), 3.73 (2.0H, s), 3.42 (4.OH, t, J = 6.1 Hz), 3.22 (3.0H, s), 3.22 (3.OH, 9), 2.66 (4.OH, t, J = 6.1 Hz), 2.53 (3.OH, s).
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 43 43
- [5-am¡no-1-(2-metil- 1 H-bendmidazol-5-il)- 1H-p¡razol-4-¡l]-{6- [(metil-prop-2- in¡lamino)-met¡l]-1 H- indol-2-¡l}-metanona 438 1H-RMN (CD30D) 6: 8.27 (1.0H, s), 7.71-7.65 (3.0K m),7.47 (1.0H, s), 7.40- 7.36 (2.OH, m), 7.13 (1.0H, dd, J = 8.1, 1.2 Hz), 3.73 (2.OH, s), 3.32-3.30 (2.0H, m), 2.73 (1.0H, t, J = 2.4 Hz), 2.62 (3.0H, s), 2.38 (3.OH, s), [5-am-1-1 (2-methyl- 1 H-bendmidazol-5-yl) - 1 H-p.razol-4-¡] - {6- [(methyl-prop-2-in-lamino] ) -met¡l] -1 H- indole-2-¡l} -methanone 438 1H-NMR (CD30D) 6: 8.27 (1.0H, s), 7.71-7.65 (3.0Km), 7.47 (1.0H, s), 7.40- 7.36 (2.OH, m), 7.13 (1.0H, dd, J = 8.1, 1.2 Hz), 3.73 (2.OH, s), 3.32-3.30 (2.0H, m), 2.73 ( 1.0H, t, J = 2.4 Hz), 2.62 (3.0H, s), 2.38 (3.OH, s),
- 44 44
- q~có ir ■ri [5-am¡no-1-(2-metil- 1 H-bendmidazol-5-il)- 1 H-pirazol-4-il]-[6- (3,3-difluoro-pirrolidin- 1-ilmetil)-1 H-indol-2- il]-1-metanona 476 1 H-RMN(DMSO-D6) 8: 12.47 (10H, brs), 1167(1.OH, br s), 8.30 (1.0H, s), 7.65- 7.63 (3.OH, m), 7.43 (1.0H, br s), 7.42 (1.0H, br s), 7.29 (1.0H, dd, J = 8.5, 1.7 Hz), 7.06-6.99 (3.0H, m), 3.71 (2.0H, s), 2.87 (2.OH, t, J = 13-4 Hz), 2.71 (2.0H, t, J = 7.1 Hz), 2.53 (3.OH, s), 2.33-2.20 (2.OH, m). q ~ co go ■ ri [5-amine-1- (2-methyl- 1 H-bendmidazol-5-yl) - 1 H-pyrazol-4-yl] - [6- (3,3-difluoro- pyrrolidin-1-ylmethyl) -1 H-indol-2- yl] -1-methanone 476 1 H-NMR (DMSO-D6) 8: 12.47 (10H, brs), 1167 (1.OH, br s), 8.30 (1.0H, s), 7.65- 7.63 (3.OH, m), 7.43 (1.0H, br s), 7.42 (1.0H, br s), 7.29 (1.0H, dd, J = 8.5, 1.7 Hz) , 7.06-6.99 (3.0H, m), 3.71 (2.0H, s), 2.87 (2.OH, t, J = 13-4 Hz), 2.71 (2.0H, t, J = 7.1 Hz), 2.53 ( 3.OH, s), 2.33-2.20 (2.OH, m).
- 45 Four. Five
- [5-am¡no-1-(2-metil- 1H-benc¡m¡dazol- 5- il)-1H-p¡razol-4-il] -[6- (2,5-d¡met¡l-1- pirrol¡d¡n-1-¡lmetil)-1H- indol-2-¡l]-metanona 468 1H-RMN (DMSO-D6) 8: 12.47 (1.0H, br s), 11.56 (1.0H, br s), 8.29 (1.0H, s), 7.67-7.59 (3.OH, m), 7.46-7.41 (2.0H, m), 7.30 (1.0H, d, J = 8.8 Hz), 7.11-6.97 (3.OH, m), 3.93-3.51 (2.0H, m), 3.02-2.94 (1.0H, m), 2.63-2.57 (3.0H, m), 2.53 (3.OH, s), 2.00-1.93 (1.0H, m), 1.84-1.76 (1.0H, m), 1.36-1.28 (2.0H, m), 0.97 (3.OH, d, J = 6.1 Hz), 0.96 (3.0H, d, J = 6.1 Hz). [5-am-1-1 (2-methyl-1 H -benzyldazol-5- yl) -1 H-p.razole-4-yl] - [6- (2,5-d-meth] l-1- pyrrol¡d¡n-1-lmethyl) -1H- indole-2-¡l] -methanone 468 1H-NMR (DMSO-D6) 8: 12.47 (1.0H, br s), 11.56 (1.0 H, br s), 8.29 (1.0H, s), 7.67-7.59 (3.OH, m), 7.46-7.41 (2.0H, m), 7.30 (1.0H, d, J = 8.8 Hz), 7.11- 6.97 (3.OH, m), 3.93-3.51 (2.0H, m), 3.02-2.94 (1.0H, m), 2.63-2.57 (3.0H, m), 2.53 (3.OH, s), 2.00- 1.93 (1.0H, m), 1.84-1.76 (1.0H, m), 1.36-1.28 (2.0H, m), 0.97 (3.OH, d, J = 6.1 Hz), 0.96 (3.0H, d, J = 6.1 Hz).
- 46 46
- Q'txK^ K vtOO- [5-amino-1-(1-met¡l- IH-bencimidazol- 5- il)-1 H-pirazol-4-il] -[6- (3,3-difl uoro-piperidin- 1-ilmetil)-1 H-indol-2- ilj-metanona 490 1H-RMN (DMSO-D6) 8:12.47 (10H, br s), 17.67 (1.0H, br s), 8.30 (1.0H, s), 7.66- 7.62 (3.OH, m), 7.43 (1.0H, br s), 7.41 (1.0H, br s), 7.29 (1.0H, dd, J = 8.8, 2.0 Hz), 7.05-7.00 (3.OH, m), 3.66 (2.0H, s), 2.64 (2.OH, t, J =12.2 Hz), 2.55 (3.0H, s), 2.44-2.42 (2.OH, m), 1.93-1.83 (2.0H, m), 1.69-1.63 (2.OH, m). Q'txK ^ K vtOO- [5-amino-1- (1-methyl-IH-benzimidazol- 5- yl) -1 H -pyrazol-4-yl] - [6- (3,3-difl uoro -piperidin- 1-ylmethyl) -1 H-indol-2- ilj-methanone 490 1 H-NMR (DMSO-D6) 8: 12.47 (10H, br s), 17.67 (1.0H, br s), 8.30 (1.0H , s), 7.66- 7.62 (3.OH, m), 7.43 (1.0H, br s), 7.41 (1.0H, br s), 7.29 (1.0H, dd, J = 8.8, 2.0 Hz), 7.05- 7.00 (3.OH, m), 3.66 (2.0H, s), 2.64 (2.OH, t, J = 12.2 Hz), 2.55 (3.0H, s), 2.44-2.42 (2.OH, m), 1.93-1.83 (2.0H, m), 1.69-1.63 (2.OH, m).
- 47 47
- ó'XKytr ™xxy [5-amino-1-(2-met¡l- 1 H-bendmidazol-5-il)- 1 H-p¡razol-4-M] -[6- ((S)-3-metll-morfolln- 4-ilmetil)-1 H-indol-2- ilj-metanona 470 1H-RMN (DMS0-D6) 8: 12.47 (1 OH, br s), 11.62 (1 .OH, br s), 8.30 (1 .OH, s), 7.64-7.58 (3.OH. m), 7.42 (1.0H. br s). 7.42 (10H, brs). 7.29 (1 .OH, d, J 8.8 Hz), 7.07-6.98 (3.OH, m), 4.12-4.09 (1 .OH, br m), 3.66-3.60 (2.0H, m), 3.46-3.40 (1 .OH, m), 3.20-3.14 (3.0H, m), 2.63 (3.0H, s), 2.44-2.40 (1 .OH, m), 2.14-2.07 (1 OH, m), 1.05-1.04 (3.OH, br m). ó'XKytr ™ xxy [5-amino-1- (2-meti-1 H-bendmidazol-5-yl) - 1 Hp¡razol-4-M] - [6- ((S) -3-metll -morfolln- 4-ylmethyl) -1 H-indol-2- yl-methanone 470 1 H-NMR (DMS0-D6) 8: 12.47 (1 OH, br s), 11.62 (1 .OH, br s), 8.30 ( 1 .OH, s), 7.64-7.58 (3.OH.m), 7.42 (1.0H. Br s). 7.42 (10H, brs). 7.29 (1 .OH, d, J 8.8 Hz), 7.07-6.98 (3.OH, m), 4.12-4.09 (1 .OH, br m), 3.66-3.60 (2.0H, m), 3.46-3.40 ( 1 .OH, m), 3.20-3.14 (3.0H, m), 2.63 (3.0H, s), 2.44-2.40 (1 .OH, m), 2.14-2.07 (1 OH, m), 1.05-1.04 ( 3.OH, br m).
- 48 48
- "xxH», ^■oír [5-amino-1-(2-met¡l- IH-bencimidazol- 5- il)-1H-pirazol-4-¡l] -(6- bromo-1 H-indol-2-il)- metanona 435, 437 1H-RMN (DMS0-D6) 8:12.48 (1H, s), 11.86 (1H, s), 8.32 (1H, d, J = 3.1 Hz), 7.68 (1H, d, J = =3.6 Hz), 7.65 (2H, br s), 7.58-7.56 (1H, m), 7.50 (1H, br s), 7.30- 7.28 (1H, m), 7.22 (1H, dd, J = 8.6, 1.6 Hz), 7.05 (2H, d, J =14.2 Hz), 2.53 (3H, s) "xxH», ^ ■ hear [5-amino-1- (2-methyl-IH-benzimidazol- 5- yl) -1H-pyrazol-4-yl] - (6- bromo-1 H-indole- 2-yl) - methanone 435, 437 1H-NMR (DMS0-D6) 8: 12.48 (1H, s), 11.86 (1H, s), 8.32 (1H, d, J = 3.1 Hz), 7.68 (1H, d , J = = 3.6 Hz), 7.65 (2H, br s), 7.58-7.56 (1H, m), 7.50 (1H, br s), 7.30- 7.28 (1H, m), 7.22 (1H, dd, J = 8.6, 1.6 Hz), 7.05 (2H, d, J = 14.2 Hz), 2.53 (3H, s)
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 49 49
- [5-amlno-1-(2-metll- 1H-benc¡m¡dazol-5-¡l)- 1 H-pirazol-4-il] -(5- yodo-1 H-indol-2-il)- metanona 483 1H-RMN (DMSO-D6) 8: 12.45 (1 .OH, s), 11.87 (1 .OH, s), 8.26 (1.1H, d, J = 4.7 Hz), 8.06 (1 OH, d, J =1.8 Hz), 7.65 (1 .OH, d, J = 8.4 Hz), 7.56 (1 OH, t, J = 4.1 Hz), 7.50 (1 .OH, dd, J = 8.6, 1.6 Hz), 7.39 (1 .OH, s), 7.33 (1 .OH, d, J = 8.6 Hz), 7.28 (1 .OH, m), 7.01 (2.OH, m), 2.63 (3.0H, d, J 1.0 Hz). [5-amlno-1- (2-metll-1H-benzmdadazol-5-l) - 1 H -pyrazol-4-yl] - (5- iodine-1 H-indole-2-yl) - methanone 483 1 H-NMR (DMSO-D6) 8: 12.45 (1 .OH, s), 11.87 (1 .OH, s), 8.26 (1.1H, d, J = 4.7 Hz), 8.06 (1 OH, d , J = 1.8 Hz), 7.65 (1 .OH, d, J = 8.4 Hz), 7.56 (1 OH, t, J = 4.1 Hz), 7.50 (1 .OH, dd, J = 8.6, 1.6 Hz), 7.39 (1 .OH, s), 7.33 (1 .OH, d, J = 8.6 Hz), 7.28 (1 .OH, m), 7.01 (2.OH, m), 2.63 (3.0H, d, J 1.0 Hz)
- 50 fifty
- [5-amino-1-(2-met¡l- 1H-bencim¡dazol-5-¡l)- 1 H-pirazol-4-il]—(1H- pirrolo[3,2-b] pi ridi n-2- ¡l)-metanona 358 1H-RMN (CD30D) 8:9.02-8.98 (1H, m), 8.31 (1H, s), 8.25 (1H, d, J = 5.9 Hz), 7.70-7.65 (2H, m), 7.59-7.56 (2H, m), 7.51 (1H, d, J = 5.9 Hz), 7.39 (1H, dd, J =8.8, 2.0Hz), 2.62 (3H, s). [5-amino-1- (2-methyl-1H-benzimdazol-5-l) - 1 H -pyrazol-4-yl] - (1H- pyrrolo [3,2-b] pi ridi n -2- ¡l) -methanone 358 1H-NMR (CD30D) 8: 9.02-8.98 (1H, m), 8.31 (1H, s), 8.25 (1H, d, J = 5.9 Hz), 7.70-7.65 (2H , m), 7.59-7.56 (2H, m), 7.51 (1H, d, J = 5.9 Hz), 7.39 (1H, dd, J = 8.8, 2.0Hz), 2.62 (3H, s).
- 51 51
- 'boU~ ®x%r [5-amino-1-(2-met¡l- 1 H-bencimidazol-5-il)- 1 H-pirazol-4-il] -(5- bromo-6-trifluorometil- 1 H-i ndol-2-il)- metanona 503, 505 1H-RMN (DMSO-D6) 8: 12.49 (1 .OH, br s), 12.33 (1 .OH, brs), 8.30 (1 .OH, s), 8.17 (1 .OH, s), 7.94 (1 .OH, s), 7.62-7.52 (3.0H, m), 7.29 (1 .OH, dd, J = 8.5, 1.7 Hz), 7.12 (2.OH, brs), 2.53 (3.0H, s). 'boU ~ ®x% r [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) - 1 H -pyrazol-4-yl] - (5- bromo-6-trifluoromethyl- 1 Hi ndol-2-yl) - methanone 503, 505 1 H-NMR (DMSO-D6) 8: 12.49 (1 .OH, br s), 12.33 (1 .OH, brs), 8.30 (1 .OH, s) , 8.17 (1 .OH, s), 7.94 (1 .OH, s), 7.62-7.52 (3.0H, m), 7.29 (1 .OH, dd, J = 8.5, 1.7 Hz), 7.12 (2.OH , brs), 2.53 (3.0H, s).
- 52 52
- li r-H. .-tpWr [5-am¡no-1-(2-met¡l- 1 H-bencimidazol-5-il)- 1H-p¡razol-4-¡l] -(6- yodo-1 H-¡ndol-2-il)- metanona 483 1H-MMR (DMSO-D6) 8: 12.43 (1.0H, s), 11.77 (1.0H, s), 8.30 (1.H, s), 7.86 (1.0H, s), 7.58 (3.OH, m), 7.46 (1.0H, s), 7.36 (1.0H, dd, J = 8.4,16 Hz), 7.29 (1.0H, m), 7.06-6.90 (2.OH, m), 2.53 (3.0H, s). li r-H. .-tpWr [5-amine-1- (2-methyl-1 H-benzimidazol-5-yl) - 1 H -pyrazol-4-l] - (6- iodine-1 H-¡ ndol-2-yl) - methanone 483 1H-MMR (DMSO-D6) 8: 12.43 (1.0H, s), 11.77 (1.0H, s), 8.30 (1.H, s), 7.86 (1.0H, s ), 7.58 (3.OH, m), 7.46 (1.0H, s), 7.36 (1.0H, dd, J = 8.4.16 Hz), 7.29 (1.0H, m), 7.06-6.90 (2.OH, m), 2.53 (3.0H, s).
- 53 53
- t^í'Cü- [5-am¡no-1-(2-met¡l- 1 H-bencimidazol-5-il)- 1H-p¡razol-4-¡l] -(4- metil-1 H-indol-2-N)- metanona 371 1H-RMN (DMSO-D6) 8: 12.47 (1.0H, br s),11.66(1.OH, br), 8.40 (1.0H, s), 7.62- 7.60 (2.OH, m), 7.46 (1.0H, s), 7.30-7.28 (2.OH, m), 7.14 (1.0H, dd, J = 7.3, 7.3 Hz), 6.99 12.OH, br s), 6.86 (1.0H, d, J = 7.3 Hz), 2.57 (3.OH, s), 2.53 (3.0H, s). t ^ í'Cü- [5-amine-1- (2-methyl-1 H-benzimidazol-5-yl) - 1 H -pyrazol-4-l] - (4- methyl-1 H-indole-2-N) - methanone 371 1 H-NMR (DMSO-D6) 8: 12.47 (1.0H, br s), 11.66 (1.OH, br), 8.40 (1.0H, s), 7.62- 7.60 (2.OH, m), 7.46 (1.0H, s), 7.30-7.28 (2.OH, m), 7.14 (1.0H, dd, J = 7.3, 7.3 Hz), 6.99 12.OH, br s) , 6.86 (1.0H, d, J = 7.3 Hz), 2.57 (3.OH, s), 2.53 (3.0H, s).
- 54 54
- C^.Í^’r ck [5-am¡no-1-(2-met¡l- 1 H-bencimidazol-5-il)- 1H-p¡razol-4-¡l] -(4- isopropil-1 H-indol-2-il)- metanona 399 1H-RMN (DMSO-D6) 8: 12.47 (1.0H, br s), 11.69 (1.0H, br s), 8.23 (1.0H, s), 7.64-7.59 (2.OH, m), 7.29 (1.0H, dd, J 8.3, 1.5 Hz), 7.25 (1.0H, brs), 7.15 (1.0H, dd, J = 8.0, 8.0 Hz), 7.04-f¡.97 (3.0H, m), 6.55 (1 .OH, d, J = 8.0 Hz), 4.79-4.73 (1.0H, m), 2.53 (3.0H, s), 1.39 (6.0H, d, J =5.9 Hz). C ^ .Í ^ 'r ck [5-amine-1- (2-methyl-1 H-benzimidazol-5-yl) - 1 H -pyrazol-4-l] - (4- isopropyl -1 H-indole-2-yl) - methanone 399 1H-NMR (DMSO-D6) 8: 12.47 (1.0H, br s), 11.69 (1.0H, br s), 8.23 (1.0H, s), 7.64 -7.59 (2.OH, m), 7.29 (1.0H, dd, J 8.3, 1.5 Hz), 7.25 (1.0H, brs), 7.15 (1.0H, dd, J = 8.0, 8.0 Hz), 7.04-f .97 (3.0H, m), 6.55 (1 .OH, d, J = 8.0 Hz), 4.79-4.73 (1.0H, m), 2.53 (3.0H, s), 1.39 (6.0H, d, J = 5.9 Hz).
- 55 55
- F j^üJl 0 B [5-amino-1-(2-met¡l- 1 H-bencimidazol-5-il)- 1H-pirazol-4-¡l] -[5-(2- fluoro-fenil)-1 H-indol- 2-il] -metanona 451 1H-RMN (DMSO-D6) 8: 12.45 (1H, br s), 11.82 (1H, s), 8.32 (1H, d, J = 4.9 Hz), 7.85(1 H, s), 7.65-7.63 (1H, m), 7.68-7.62 (4H, m), 7.44-7.42 (1H, m), 7.39-7.35 (1H, m), 7.31-7.28 (3H, m), 7.04 (1H, br s), 6.99 (1H, br s), 2.52 (3H, s). F j ^ üJl 0 B [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) - 1 H -pyrazol-4-α] - [5- (2- fluoro-phenyl) -1 H-indole-2-yl] -methanone 451 1H-NMR (DMSO-D6) 8: 12.45 (1H, br s), 11.82 (1H, s), 8.32 (1H, d, J = 4.9 Hz), 7.85 (1 H, s), 7.65-7.63 (1H, m), 7.68-7.62 (4H, m), 7.44-7.42 (1H, m), 7.39-7.35 (1H, m), 7.31-7.28 (3H, m), 7.04 (1H, br s), 6.99 (1H, br s), 2.52 (3H, s).
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 56 56
- [5-amino-1-(2-metil- 1Nbencimidazol-5-il)- 1 H-pirazol-4-il] -(5- bencil-1 H-indol-2-il)- metanona 447 1H-MMR (DMSO-D6) 8: 12.47 (1H, br s), 11.6.2 (1H, br s), 8.29 (1H, s), 7.69-7.53 (2H, m), 7.52-7.48 (1H, m), 7.42.- 7.36 (2H, m), 7.32-7.23 (5H, m), 7.20-7.12 (2H, m), 7.06-6.93 (2H, m), 4.02 (2H, s), 2.53 (3H, s). [5-amino-1- (2-methyl-1Nbenzimidazol-5-yl) -1 H -pyrazol-4-yl] - (5- benzyl-1 H-indole-2-yl) -methanone 447 1H-MMR ( DMSO-D6) 8: 12.47 (1H, br s), 11.6.2 (1H, br s), 8.29 (1H, s), 7.69-7.53 (2H, m), 7.52-7.48 (1H, m), 7.42 .- 7.36 (2H, m), 7.32-7.23 (5H, m), 7.20-7.12 (2H, m), 7.06-6.93 (2H, m), 4.02 (2H, s), 2.53 (3H, s).
- 57 57
- 4srvl o a H [5-amino-1-(2-metil- 1 H-bencimidazol-5-il)- 1 H-pirazol-4-il] -[5-(2- trifl uorometil-fenil)-1 H- indol-2-il]-metanona 501 1H-RMN (DMSO-D6) 8: 12.48 (1H, br s), 11.82 (1H, s), 8.31 (1H, s), 7.83.7.81 (1H, m), 7-72.770 (1H, m), 7.60-7.57 (4H, m), 7.52-7.50 (2H, m), 7.45 (1H, d, J = 7.2 Hz), 7.28 (1H, dd, J = 3.4, 2.0 Hz), 7.19-7.17 (1H, m), 7.01 (2H, br s), 2.52 (3H, s). 4srvl or H [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) - 1 H -pyrazol-4-yl] - [5- (2- trifl uoromethyl-phenyl) -1 H- indole-2-yl] -methanone 501 1H-NMR (DMSO-D6) 8: 12.48 (1H, br s), 11.82 (1H, s), 8.31 (1H, s), 7.83.7.81 (1H, m), 7-72.770 (1H, m), 7.60-7.57 (4H, m), 7.52-7.50 (2H, m), 7.45 (1H, d, J = 7.2 Hz), 7.28 (1H, dd, J = 3.4, 2.0 Hz), 7.19-7.17 (1H, m), 7.01 (2H, br s), 2.52 (3H, s).
- 58 58
- [5-amino-1-(2-metil- 1 H-bencimidazol-5-il)- 1 H-pirazol-4-il] -[5-(3- fluorofenil)-1 H-indol-2- il] -metanona 451 1H-RMN (DMSO-D6] 8: 12.47 (1H, s), 11.81 (1H, s), 8.30 (1H, s), 7.99 (1H,s), 7.61-7.46(8H,m), 1.28(1H,dd,J=8.4,1.8Hz), 7.15-7.12 (1H,m), 7.01 (2H, br s), 2.52 (3H s). [5-amino-1- (2-methyl- 1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [5- (3- fluorophenyl) -1 H-indole-2- yl] -methanone 451 1 H-NMR (DMSO-D6] 8: 12.47 (1H, s), 11.81 (1H, s), 8.30 (1H, s), 7.99 (1H, s), 7.61-7.46 (8H, m), 1.28 (1H, dd, J = 8.4.1.8Hz), 7.15-7.12 (1H, m), 7.01 (2H, br s), 2.52 (3H s).
- 59 59
- [5-amino-1-(2-metil- 1 H-bencimidazol-5-il)- 1 H-pirazol-4-il] -[5-(3- trifluorometil-fenil)-1 H- indol-2-il]-metanona 501 1H-RMN (DMSO-D6) 8: 12.48 (1H, br s), 11. 24 (1H, s), 8.29 (1H, s), 8.05 (1H, d, J = 1.3 Hz), 8.62-8.00 (1H, m), 7.97 (1H, s), 7.72-7.58 (6H, m). 7.61 (1H, s), 7.28 (1H, dd, J =8.4. 2.2 Hz), 7.02 (2H, s), 2.52 (3H, s). [5-amino-1- (2-methyl- 1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [5- (3- trifluoromethyl-phenyl) -1 H- indole-2- il] -methanone 501 1H-NMR (DMSO-D6) 8: 12.48 (1H, br s), 11. 24 (1H, s), 8.29 (1H, s), 8.05 (1H, d, J = 1.3 Hz) , 8.62-8.00 (1H, m), 7.97 (1H, s), 7.72-7.58 (6H, m). 7.61 (1H, s), 7.28 (1H, dd, J = 8.4. 2.2 Hz), 7.02 (2H, s), 2.52 (3H, s).
- 60 60
- H ?V^ H [5-amino-1-(2-metil- 1 H-bencimidazol-5-il)- 1 H-pirazol-4-il] -(4- etinil-1 H-indol-2-il)- metanona 381 1H-RMN (DMSO-D6) 8: 12.47 (1.0H, br s), 12.01 (1.0H, br s), 8.24 (1.0H, s), 7.62-7.60 (2.0H, m), 7.57-7.53 (1.0H, m), 7.31-7.24 (4.0H, m), 7.03 (2.0H, br s), 4.44 (1.0H, s), 2.53 (3.0H, s). H? V ^ H [5-amino-1- (2-methyl- 1 H -benzimidazol-5-yl) - 1 H -pyrazol-4-yl] - (4- ethynyl-1 H-indole-2-yl ) - methanone 381 1 H-NMR (DMSO-D6) 8: 12.47 (1.0H, br s), 12.01 (1.0H, br s), 8.24 (1.0H, s), 7.62-7.60 (2.0H, m), 7.57-7.53 (1.0H, m), 7.31-7.24 (4.0H, m), 7.03 (2.0H, br s), 4.44 (1.0H, s), 2.53 (3.0H, s).
- 61 61
- í4K> H [5-amino-1-(2-metil- 1 H-bencimidazol-5-il)- 1H-pirazol -4-il]-(5H- [1,3]dioxolo[4,5-f] indol-6-il)-metanona 401 1H-RMN (DMSO-D6) 8: 12.46 (1H, s), 11.52 (1H, s), 8.23 (1H, s), 7.69-7.58 (2H, m), 7.32 (1H, s), 7.27 (1H, dd, J = 8.6, 2.0 Hz), 7.07 (1H, s) 6.92 (2H, br s), 6.90 (1H, s), 5.99 (2H, s), 2.52 (3H, s). 4K> H [5-amino-1- (2-methyl- 1 H -benzimidazol-5-yl) - 1 H -pyrazol -4-yl] - (5H- [1,3] dioxolo [4,5-f] indole-6-yl) -methanone 401 1H-NMR (DMSO-D6) 8: 12.46 (1H, s), 11.52 (1H, s), 8.23 (1H, s), 7.69-7.58 (2H, m), 7.32 (1H, s), 7.27 (1H, dd, J = 8.6, 2.0 Hz), 7.07 (1H, s) 6.92 (2H, br s), 6.90 (1H, s), 5.99 (2H, s), 2.52 ( 3H, s).
- 62 62
- H Cü~>. vpí- 1 " [5-amino-1-(7-fluoro-2- metil-1H- bencimidazol-5-il)-1 H- pirazol-4-il]-(1 H-indol- 2-il)-metanona 375 1H-RMN (DMSO-D6] 8: 12.81 (1.0H, aJ, 11.68 (1.0H, s), 8.33 (1.0H, s), 7.70 (1.0H, d, J = 8.0 Hz), 7.50-7.40 (3.0H, m), 7.30-7.22 (7.4H, m), 7.18 (1.0H, d, J = 11.2 Hz), 7.09 (3.0H, m), 2.55 (3.0H, s). H Cü ~>. vpi- 1 "[5-amino-1- (7-fluoro-2- methyl-1 H- benzimidazol-5-yl) -1 H- pyrazol-4-yl] - (1 H-indole-2-yl) - methanone 375 1H-NMR (DMSO-D6] 8: 12.81 (1.0H, aJ, 11.68 (1.0H, s), 8.33 (1.0H, s), 7.70 (1.0H, d, J = 8.0 Hz), 7.50- 7.40 (3.0H, m), 7.30-7.22 (7.4H, m), 7.18 (1.0H, d, J = 11.2 Hz), 7.09 (3.0H, m), 2.55 (3.0H, s).
- Ejemplo Example
- Estructura Nombre del compuesto miz 1H-RMN Structure Name of compound miz 1H-NMR
- 63 63
- r>r02MuBi' [5-amino-1-(2-met¡l-1 H- bencimidazol- 5-¡l)-1H- pirazol -4-¡l]-[5-(4- trifluorometilfenil)-1 H-indol- 2-¡l]-metanona 501 1H-RMN (DMSO-D6) 8: 12.46 (1H, d, J. 5.3 Hz), 11.86 (1H, s), 8.31 (1H, d, J = 5.3 Hz), 8.05 (1H, s), 7.92 (2H, d, J = 8.4 Hz), 7.00 (2H, d, J )8.4 Hz), 7.63-7.57 (4H, m), 7.53 (1H, s), 7.30-7.27 (1H, m), 7.06 (1H, s), 700 (1H, s), 2.52 (3H, s). r> r02MuBi '[5-amino-1- (2-methyl-1 H- benzimidazole-5-α) -1H- pyrazole -4-αl] - [5- (4- trifluoromethylphenyl) -1 H -indole- 2-¡1] -methanone 501 1H-NMR (DMSO-D6) 8: 12.46 (1H, d, J. 5.3 Hz), 11.86 (1H, s), 8.31 (1H, d, J = 5.3 Hz ), 8.05 (1H, s), 7.92 (2H, d, J = 8.4 Hz), 7.00 (2H, d, J) 8.4 Hz), 7.63-7.57 (4H, m), 7.53 (1H, s), 7.30 -7.27 (1H, m), 7.06 (1H, s), 700 (1H, s), 2.52 (3H, s).
[Ejemplo 64: Síntesis de la [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-p¡ razol-4-il]-(5-butoxi-1 H-indol-2-il)- metanona][Example 64: Synthesis of [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hp¡ razol-4-yl] - (5-butoxy-1 H-indole-2 -il) - methanone]
55
Una mezcla que consiste en [5-am¡no-1-(2-metil-1H-benc¡midazol-5-il)-1H-p¡razol-4-¡l]-[5-butoxi-1-(tolueno-4- sulfonil )-1H-indol-2-¡l]-metanona (70 mg), dloxano (3 mi), y una solución acuosa de hidróxido de sodio 5 M (300 mi) se agitó bajo reflujo, durante dos horas. La mezcla de reacción se enfrió en un baño de hielo, y se acidificó con una solución acuosa de ácido clorhídrico 5 M. El solvente se separó por destilación bajo presión reducida. Se adicionó agua al 10 residuo obtenido por la concentración bajo presión reducida. El sólido se recolectó por filtración, se lavó con agua, y se secó para darA mixture consisting of [5-amine-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [5-butoxy-1- ( toluene-4-sulfonyl) -1H-indole-2-l] -methanone (70 mg), dloxane (3 ml), and a 5 M aqueous solution of sodium hydroxide (300 ml) was stirred under reflux for two hours. The reaction mixture was cooled in an ice bath, and acidified with a 5 M aqueous hydrochloric acid solution. The solvent was distilled off under reduced pressure. Water was added to the residue obtained by concentration under reduced pressure. The solid was collected by filtration, washed with water, and dried to give
[5-amino-1-(2-met¡l-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(5-butoxi-1H-indol-2-il)-metanona (35 mg, 65%).[5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (5-butoxy-1H-indole-2-yl) -methanone (35 mg , 65%).
1H-RMN (DMSO-De) 5: 12.45 (1H ,s), 11.54 (1H, d, J = 1.8 Hz), 8.25 (1H, s), 7.65-7.63 (1H, brm), 7.57-7.55 (1H, brm), 7.36 (1H, d, J = 8.8 Hz), 7.32 (1H, d, J = 1.8 Hz), 7.30-7.28 (1H, brm), 7.12 (1H, d, J = 2.4 Hz), 7.01 (1H, brs), 15 6.95 (1H, brs), 6.90 (1H, dd, J = 8.8, 2.4 Hz), 3.98 (2H, t, J = 6.4 Hz), 2.53 (3H, s), 1.76-1.69 (2H, m), 1.51-1.44 (2H,1H-NMR (DMSO-De) 5: 12.45 (1H, s), 11.54 (1H, d, J = 1.8 Hz), 8.25 (1H, s), 7.65-7.63 (1H, brm), 7.57-7.55 (1H , brm), 7.36 (1H, d, J = 8.8 Hz), 7.32 (1H, d, J = 1.8 Hz), 7.30-7.28 (1H, brm), 7.12 (1H, d, J = 2.4 Hz), 7.01 (1H, brs), 15 6.95 (1H, brs), 6.90 (1H, dd, J = 8.8, 2.4 Hz), 3.98 (2H, t, J = 6.4 Hz), 2.53 (3H, s), 1.76-1.69 (2H, m), 1.51-1.44 (2H,
m), 0.95 (3H, t, J = 7.3 Hz) ESI (LC-MS modo positivo) m/z 429 [(M+H)+]m), 0.95 (3H, t, J = 7.3 Hz) ESI (LC-MS positive mode) m / z 429 [(M + H) +]
Los compuestos de los Ejemplos 65 a 89, y 204 a 239 enumerados en la Tabla 3, se sintetizaron mediante el mismo método como en el Ejemplo 64.The compounds of Examples 65 to 89, and 204 to 239 listed in Table 3, were synthesized by the same method as in Example 64.
Tabla 3Table 3
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 65 65
- ti O &h|_| p [5-amino-1-(2-metil- 1 H-bencimidazol-5-il)- 1 H-pirazol-4-il] -[5-(1- metil-piperidin-4-il)- 1H-indol-2- iljmetanona 454 1H-RMN (DMSOD6) 8: 12.45 (1H, s), 11.56 (1H, d, J =1.8 Hz), 8.28 (1H, s), 7.66-7.62 (1H, br m), 7.60-7.55 (1H, br m), 7.50 (1H, d, J = 1.8 Hz), 7.40 (1H, d, J = 8.5 Hz), 7.37 (1H, d. J = 1.8 Hz), 7.29 (1H, d, J = 8.5 Hz), 7.16 (1H, dd, J = 8.5, 1.8 Hz), 7.00 (1H, br s), 6.95 (1H, br s), 2.89-2.87 (2H, m), 2.55- 2.51 (1H, br m), 2.53 (3H, s), 2.20 (3H, s), 2.01-1.95 (2H, m), 1.82-1.65 (4H, m). you O & h | _ | p [5-amino-1- (2-methyl- 1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [5- (1- methyl-piperidin-4-yl) - 1H- indole-2- iljmetanone 454 1H-NMR (DMSOD6) 8: 12.45 (1H, s), 11.56 (1H, d, J = 1.8 Hz), 8.28 (1H, s), 7.66-7.62 (1H, br m), 7.60-7.55 (1H, br m), 7.50 (1H, d, J = 1.8 Hz), 7.40 (1H, d, J = 8.5 Hz), 7.37 (1H, d. J = 1.8 Hz), 7.29 (1H, d, J = 8.5 Hz), 7.16 (1H, dd, J = 8.5, 1.8 Hz), 7.00 (1H, br s), 6.95 (1H, br s), 2.89-2.87 (2H, m), 2.55-2.51 (1H, br m), 2.53 (3H, s), 2.20 (3H, s), 2.01-1.95 (2H, m), 1.82-1.65 (4H, m).
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 66 66
- N-{2-[5-amino-1-(2-metil- 1 H-benclm¡dazol-5-il)-1 H- pirazol-4-carbonil]-1 H- indol-6-il}- metanosulfonamida 450 1H-RMN (DMSOD6) 8: 12.45 (1H, s), 11.65 (1H, s), 9.67 (1H, s), 8.28 (1H, s), 7.67-7.54 (3H, m), 7.42 (2H, s), 7.29 (1H, s), 7.02-6.93 (3H, m), 2.95 (3H, s), 2.53 (3H, s). N- {2- [5-amino-1- (2-methyl- 1 H -benzyldazol-5-yl) -1 H- pyrazol-4-carbonyl] -1 H- indole-6-yl} -methanesulfonamide 450 1H-NMR (DMSOD6) 8: 12.45 (1H, s), 11.65 (1H, s), 9.67 (1H, s), 8.28 (1H, s), 7.67-7.54 (3H, m), 7.42 (2H, s), 7.29 (1H, s), 7.02-6.93 (3H, m), 2.95 (3H, s), 2.53 (3H, s).
- 67 67
- [5-amino-1-(2-metil-1 H- bencim¡dazol-5-il)-1 H- plrazol-4-il] -[6-(6-morfolln- 4-il-piridin-3-il)-1 H-indol-2- ilj-metanona 519 1H-RMN (DMSOD6) 8: 12.48 (1H, s), ? 11.73 (1H, s), 8.49 (1H, d, J = 2.4 Hz), 8.33 (1H, s), 7.90 (1H, dd, J = 9.2, 2.4 Hz), 7.76 (1H, d, J = 7.9 Hz), 7.65-7.58 (3H, m), 7.48 (1H, s), 7.37 (1H, dd, J = 8.5, 1.2 Hz), 7.30 (1H, dd, J = 8.5, 1.8 Hz), 7.01 (2H, s), 6.96 (1H, d, J = 8.5 Hz), 3.78-3.70 (4H, m), 3.54-3.47 (4H, m), 2.54 (3H, s). [5-amino-1- (2-methyl-1 H- benzimdazol-5-yl) -1 H- plrazol-4-yl] - [6- (6-morfolln-4-yl-pyridin-3- il) -1 H-indol-2- ilj-methanone 519 1H-NMR (DMSOD6) 8: 12.48 (1H, s),? 11.73 (1H, s), 8.49 (1H, d, J = 2.4 Hz), 8.33 (1H, s), 7.90 (1H, dd, J = 9.2, 2.4 Hz), 7.76 (1H, d, J = 7.9 Hz ), 7.65-7.58 (3H, m), 7.48 (1H, s), 7.37 (1H, dd, J = 8.5, 1.2 Hz), 7.30 (1H, dd, J = 8.5, 1.8 Hz), 7.01 (2H, s), 6.96 (1H, d, J = 8.5 Hz), 3.78-3.70 (4H, m), 3.54-3.47 (4H, m), 2.54 (3H, s).
- 68 68
- [5-amino-1-(2-metll-1 H- bencim¡dazol-5-il)-1 H- pirazol-4-il] -(6-but¡l-1H- ¡ndol-2-il)-metanona 413 1H-RMN (DMSOD6) 8:12.46 (1H, s), 11.54 (1H, s), 8.28 (1H, s), 7.59-7.57 (3H, m), 7.38 (1H, d, J = 1.4 Hz), 7.28 (1H, dd, J = 8.4, 2.0 Hz), 7.25 (1H, s), 6.96 (2H, s), 6.93 (1H, dd, J 8.3, 1.5 Hz), 2.68-2.65 (2H, m), 2.52 (3H, s), 1.62-1.55 (2H, m), 1.34-1.30 (2H, m), 0.90 (3H, t, J = 7.3 Hz). [5-amino-1- (2-metll-1 H- benzimdazol-5-yl) -1 H- pyrazol-4-yl] - (6-butyl-1H- ndol-2-yl) -metanone 413 1H-NMR (DMSOD6) 8: 12.46 (1H, s), 11.54 (1H, s), 8.28 (1H, s), 7.59-7.57 (3H, m), 7.38 (1H, d, J = 1.4 Hz), 7.28 (1H, dd, J = 8.4, 2.0 Hz), 7.25 (1H, s), 6.96 (2H, s), 6.93 (1H, dd, J 8.3, 1.5 Hz), 2.68-2.65 (2H, m), 2.52 (3H, s), 1.62-1.55 (2H, m), 1.34-1.30 (2H, m), 0.90 (3H, t, J = 7.3 Hz).
- 69 69
- v‘-£Cr [5-amlno-1-(2-metil-1 H- benclmldazol-5-¡l)-1H- pirazol-4-il] -[6-(1 -metil-1 H- pirazol-4-il)-1 H-indol-2-il]- metanona 437 1H-KMN (UMoUUb) O. 12.4» (1H, S), 11.68 (1H, s), 8.31 (1H, s), 8.14 (1H, s), 7.84 (1H, s), 7.67 (1H, d. J = 8.5 Hz), 7.62-7.56 (3H, m), 7.43 (1H, s). 7.32 (1H, dd, J = 8.5, 1.2 Hz), 7.28 (1H, dd. J 8.6, 1.8 Hz), 8.99 (2H. s), 3.89 (3H, s), 2.54 (3H, s). v'- £ Cr [5-amlno-1- (2-methyl-1 H- benclmldazol-5-¡l) -1H- pyrazol-4-yl] - [6- (1-methyl-1 H- pyrazole- 4-yl) -1 H-indol-2-yl] - methanone 437 1H-KMN (UMoUUb) O. 12.4 »(1H, S), 11.68 (1H, s), 8.31 (1H, s), 8.14 (1H , s), 7.84 (1H, s), 7.67 (1H, d. J = 8.5 Hz), 7.62-7.56 (3H, m), 7.43 (1H, s). 7.32 (1H, dd, J = 8.5, 1.2 Hz), 7.28 (1H, dd. J 8.6, 1.8 Hz), 8.99 (2H. S), 3.89 (3H, s), 2.54 (3H, s).
- 70 70
- o' Mí# [5-amlno-1-(2-metll-1 H- benclmldazol-5-¡l)-1H- plrazol-4-il]-[6-(5-metox¡- pir¡din-3-il)-1 H-indol-2-il]- metanona 464 IN-mVIIN (UIVIoUUO) O. 11.0/ (1N, S), 8.51 (1H, d, J = 1.8 Hz), 8.38 (1H, s), 8.31 (1H, d, J = 3.1 Hz), 7.83 (1H, d, J = 8.5 Hz), 7.79-7.72 (3H,m), 7.64 (1H, t,J = 2.7 Hz), 7.53 (1H,d,J =1.8 Hz), 7.49-7.45 (2H, m), 7.14 (2H, s}. 3.94 {3H, s), 2.65 (3H, s). o 'Me # [5-amlno-1- (2-metll-1 H- benclmldazol-5-¡1) -1H- plrazol-4-yl] - [6- (5-methox¡- pir¡din-3 -il) -1 H-indole-2-yl] - methanone 464 IN-mVIIN (UIVIoUUO) O. 11.0 / (1N, S), 8.51 (1H, d, J = 1.8 Hz), 8.38 (1H, s) , 8.31 (1H, d, J = 3.1 Hz), 7.83 (1H, d, J = 8.5 Hz), 7.79-7.72 (3H, m), 7.64 (1H, t, J = 2.7 Hz), 7.53 (1H, d, J = 1.8 Hz), 7.49-7.45 (2H, m), 7.14 (2H, s}. 3.94 {3H, s), 2.65 (3H, s).
- 71 71
- [5-amlno-1-(2-metll-1 H-b enzim¡dazol-5-il)-1H- plrazol-4-il] -[6-(2-metox¡- piridin-3-il)-1 H-lndol-2-il]- metanona 464 In-mVIIN (UIVIoUUO) o. 11.0/ (In, S), 8.51 (1H, d, J = 1.8 Hz), 6.38 (1H, s), 8.31 (1H, d, J = 3.1 Hz), 7.83 (1H, d, J = 8.5 Hz), 7.79-7.72 (3H,m), 7.64 (1H, t, J = 2.1 Hz), 7.53 (1H, d, J = 1.8 Hz), 7.49-7.45 (2H, m), 7.14 (2H, s), 3.94 (3H, s), 2.65 (3H, s). [5-amlno-1- (2-metll-1 Hb enzymdadazol-5-yl) -1 H- plrazol-4-yl] - [6- (2-methoxy-pyridin-3-yl) -1 H -lndol-2-il] - methanone 464 In-mVIIN (UIVIoUUO) or. 11.0 / (In, S), 8.51 (1H, d, J = 1.8 Hz), 6.38 (1H, s), 8.31 (1H, d, J = 3.1 Hz), 7.83 (1H, d, J = 8.5 Hz) , 7.79-7.72 (3H, m), 7.64 (1H, t, J = 2.1 Hz), 7.53 (1H, d, J = 1.8 Hz), 7.49-7.45 (2H, m), 7.14 (2H, s), 3.94 (3H, s), 2.65 (3H, s).
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 72 72
- [5-amino-1-(2-met¡l-1H- bencim¡dazol-5-¡l)-1H- pirazol-4-ll] -(6-clclopropil- 1 H-indol-2-ll)-metanona 397 1H-RMN (DMSOD6) 8: 12.46 (1H, s), 11.49 (1H, s), 8.27 (1H, s), 7.69 (1H, br s), 7.66 (1H, s), 7.54 (1H, s), 7.37 (1H, d, J = 1.4 Hz), 7.27 (1H, dd, J = 8.5, 2.1 Hz), 7.16 (1H, s), 8.95 (2H, br s), 6.80 (1H, dd, J = 8.4, 1.6 Hz), 2.52 (3H, s), 2.04-1.97 (1H, m), 0.96 (2H. ddd, J = 9.5, 5.2, 3.0 Hz), 0.69-0.65 (2H, m). [5-amino-1- (2-methyl-1H-benzimdazol-5-l) -1 H- pyrazol-4-ll] - (6-clclopropyl-1 H-indole-2-ll) - methanone 397 1H-NMR (DMSOD6) 8: 12.46 (1H, s), 11.49 (1H, s), 8.27 (1H, s), 7.69 (1H, br s), 7.66 (1H, s), 7.54 (1H, s), 7.37 (1H, d, J = 1.4 Hz), 7.27 (1H, dd, J = 8.5, 2.1 Hz), 7.16 (1H, s), 8.95 (2H, br s), 6.80 (1H, dd, J = 8.4, 1.6 Hz), 2.52 (3H, s), 2.04-1.97 (1H, m), 0.96 (2H. Ddd, J = 9.5, 5.2, 3.0 Hz), 0.69-0.65 (2H, m).
- 73 73
- '"J,-CCr M [5-amino-1-(2-met¡l-1H- bencimidazol-5-¡l)-1H- plrazol-4-il] -[6-(2-metox¡- fenil)-1 H-indol-2-il]- metanona 463 1H-RMN (DMSOD6) 8: 12.49 (1H, s), 11.71 (1H, s), 8.34 (1H, s), 7.75-7.55 (4H, m), 7.48 (1H, s), T.40-7.28 (3H, m}, 7.20 j1H, d, J= 8.5 Hz), 7.13 (1H, d, J =8.5 Hz), 7.09-6.98 (3H, m), 3.78 (3H, s), 2.54 (3H, s), '"J, -CCr M [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 H- plrazol-4-yl] - [6- (2-methoxy-phenyl) ) -1 H-indole-2-yl] - methanone 463 1H-NMR (DMSOD6) 8: 12.49 (1H, s), 11.71 (1H, s), 8.34 (1H, s), 7.75-7.55 (4H, m ), 7.48 (1H, s), T.40-7.28 (3H, m}, 7.20 j1H, d, J = 8.5 Hz), 7.13 (1H, d, J = 8.5 Hz), 7.09-6.98 (3H, m ), 3.78 (3H, s), 2.54 (3H, s),
- 74 74
- C^CrHr ”"&r [5-amino-1-(2-met¡l-1H- bencimidazol-5-il)-1 H- plrazol-4-il] -(6-fen¡l-1H- ¡ndol-2-il)-metanona 433 1H-RMN (DMSOD6) 8: 12.49 (1H, s), 11.80 (1H, s), 8.34 (1H, s), 7.79 (1H, d, J = 8.5 Hz), 7.73-7.60 (5H, s), 7.62-7.47 (3H, m), 7.41 (1H, dd, J = 8.5, 1.2 Hz), 7.37 (1H, t, J = 7.3 Hz), 7.30 (1H, dd, J = 8.2, 2.1 Hz), 7.04 (2H, s), 2.54 (3H, s}.. C ^ CrHr "" & r [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1 H- plrazol-4-yl] - (6-phenol-1H- ndol -2-yl) -methanone 433 1H-NMR (DMSOD6) 8: 12.49 (1H, s), 11.80 (1H, s), 8.34 (1H, s), 7.79 (1H, d, J = 8.5 Hz), 7.73 -7.60 (5H, s), 7.62-7.47 (3H, m), 7.41 (1H, dd, J = 8.5, 1.2 Hz), 7.37 (1H, t, J = 7.3 Hz), 7.30 (1H, dd, J = 8.2, 2.1 Hz), 7.04 (2H, s), 2.54 (3H, s} ..
- 75 75
- A,X¡- [5-amlno-1-(2-met¡l-1H- benclmldazol-5-¡l)-1H- pirazol-4-il] -[6-(5- metanosulfonilo-piridin-3- ¡I) -1 H-¡ndol-2-il]- metanona 512 1H-RMN (DMSOD6) 8: 12.48 (1H, s), 11.97 (1H, s), 9.26 (1H, s), 9.06 (1H, s), 8.55 (1H, s), 8.35 (1 H, d, J = 3.7 Hz), 7.93-7.84 (2H, m), 7.70-7.51 (4H, m), 7.31 (1H, t, J = 7.0 Hz), 7.09 (1H, s), 7.03 (1H, s), 3.44 (3H, s), 2.54 (3H, s). A, X¡- [5-amlno-1- (2-methyl-1H- benclmldazol-5-¡l) -1H- pyrazol-4-yl] - [6- (5- methanesulfonyl-pyridin-3- I) -1 H-¡ndol-2-yl] - methanone 512 1H-NMR (DMSOD6) 8: 12.48 (1H, s), 11.97 (1H, s), 9.26 (1H, s), 9.06 (1H, s), 8.55 (1H, s), 8.35 (1 H, d, J = 3.7 Hz), 7.93-7.84 (2H, m), 7.70-7.51 (4H, m), 7.31 (1H, t, J = 7.0 Hz), 7.09 (1H, s), 7.03 (1H, s), 3.44 (3H, s), 2.54 (3H, s).
- 76 76
- [5-amino-1-(2-met¡l-1H- bencimidazol-5-¡l)-1 H- p¡razol-4-il]-(6-¡sopropil- 1 H-¡ndol-2-il)-metanona 399 1H-RMN (DMSOD6) 8: 12.46 (1H, s), 11.54 (1H, s), 8.27 (1H, s), 7.60-7.58 (3H, m), 7.38 (1H, d, J = 1.6 Hz), 7.29- 7.26 (2H, m), 7.00 (1H, dd, J = 8.5, 1.5 Hz), 6.96 (2H, br s), 3.01-2.94 (1H, m), 2.52 (3H, s), 1.26 (3H, s), 1.24 (3H, s). [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 H- p¡razol-4-yl] - (6-sopropyl-1 H-lozenol-2- il) -methanone 399 1H-NMR (DMSOD6) 8: 12.46 (1H, s), 11.54 (1H, s), 8.27 (1H, s), 7.60-7.58 (3H, m), 7.38 (1H, d, J = 1.6 Hz), 7.29- 7.26 (2H, m), 7.00 (1H, dd, J = 8.5, 1.5 Hz), 6.96 (2H, br s), 3.01-2.94 (1H, m), 2.52 (3H, s ), 1.26 (3H, s), 1.24 (3H, s).
- 77 77
- v-o^ [5-am¡no-1-(2-met¡l-1H- bencimidazol- 5-¡l)-1H- p¡razol-4-il] -(6-p¡r¡d¡n-2-M- 1 H-lndol-2-il)-metanona 434 1H-RMN (DMSOD6) 8: 12.49 (1H, s), 11.91 (1H, s), 8.68 (1H, d, J = 4.9 Hz), 8.34 (1H, s), 8.26 (1H, s), 7.97 (1H, d, J = 7.9 Hz), 7.91-7.87 (1H, m), 7.81 (2H, q, J = 8.5 Hz), 7.63 (2H, s), 7.50 (1H, s), 7.36-7.28 (2H, m), 7.04 (2H, s), 2.54 (3H, s). vo ^ [5-am-no-1- (2-methyl-1H-benzimidazol-5-l) -1 H- p¡razol-4-yl] - (6-p¡r¡d¡n- 2-M- 1 H-lndol-2-yl) -methanone 434 1H-NMR (DMSOD6) 8: 12.49 (1H, s), 11.91 (1H, s), 8.68 (1H, d, J = 4.9 Hz), 8.34 (1H, s), 8.26 (1H, s), 7.97 (1H, d, J = 7.9 Hz), 7.91-7.87 (1H, m), 7.81 (2H, q, J = 8.5 Hz), 7.63 (2H , s), 7.50 (1H, s), 7.36-7.28 (2H, m), 7.04 (2H, s), 2.54 (3H, s).
EjemploExample
EstructuraStructure
Nombre del compuestoCompound Name
m/zm / z
1H-RMN1 H-NMR
lí «h.l «h.
7878
■■"XI-t■■ "XI-t
[5-am¡no-1-(2-metil-1 H- bencimidazol- 5-il)-1H- pirazol-4-il] -(5-ciclopropil- 1 H-¡ndol-2-ll)-metanona[5-am-1-1 (2-methyl-1 H- benzimidazol-5-yl) -1 H- pyrazol-4-yl] - (5-cyclopropyl-1 H-lendol-2-ll) -methanone
397397
1H-RMN (DMSOD6) 8: 12.48 (1H, s), 11.58 (1H, s), 8.27 (1H, s), 7.64-7.57 (2H, br m), 7.37 (1H, s), 7.36 (1H, d, J = 8.5 Hz), 7.33 (1H, d, J = 1.5 Hz), 7.28 (1H, dd, J = 8.2, 2.1 Hz), 7.00 (1H, dd, J = 8.5, 1.5 Hz), 6.99 (2H, br s), 2.53 (3H, s),2.03-1.97 (1H, m), 0.95-0.90 (2H, m), 0.68-0.64 (2H, m).1H-NMR (DMSOD6) 8: 12.48 (1H, s), 11.58 (1H, s), 8.27 (1H, s), 7.64-7.57 (2H, br m), 7.37 (1H, s), 7.36 (1H, d, J = 8.5 Hz), 7.33 (1H, d, J = 1.5 Hz), 7.28 (1H, dd, J = 8.2, 2.1 Hz), 7.00 (1H, dd, J = 8.5, 1.5 Hz), 6.99 ( 2H, br s), 2.53 (3H, s), 2.03-1.97 (1H, m), 0.95-0.90 (2H, m), 0.68-0.64 (2H, m).
7979
KK
v'tSrv'tSr
[5-amino-1-(2-met¡l-1 H- bencim¡dazol-5-il)-1 H- plrazol-4-il] -(6-plrldazln- 3-H-1 H-indol-2-il)- metanona[5-amino-1- (2-methyl-1 H- benzimdazol-5-yl) -1 H- plrazol-4-yl] - (6-plrldazln- 3-H-1 H-indole- 2-il) - methanone
435435
1H-RMN (DMSOD6) 8: 12.49 (1H, s), 12.03 (1H, s), 9.20 (1H, dd, J = 4.9, 1.5 Hz), 8.35 (2H, d, J = 8.0 Hz), 8.24 (1H, d, J = 8.5 Hz), 7.87 (2H, s), 7.78 (1H, dd, J = 8.5, 4.9 Hz), 7.63 (1H, s), 7.54 (2H, s), 7.31 (1H, dd, J = 8.0, 1.5 Hz), 7.06 (2H,s), 2.54 (3H, s).1H-NMR (DMSOD6) 8: 12.49 (1H, s), 12.03 (1H, s), 9.20 (1H, dd, J = 4.9, 1.5 Hz), 8.35 (2H, d, J = 8.0 Hz), 8.24 ( 1H, d, J = 8.5 Hz), 7.87 (2H, s), 7.78 (1H, dd, J = 8.5, 4.9 Hz), 7.63 (1H, s), 7.54 (2H, s), 7.31 (1H, dd , J = 8.0, 1.5 Hz), 7.06 (2H, s), 2.54 (3H, s).
«o"or
[5-am¡no-1-(2-metil-1 H- bencimldazol-5-¡l)1H- pirazol-4-ll] -(5- isopropoxi-1 H-lndol-2-ll)- metanona[5-am-1-1 (2-methyl-1 H- benzimdazol-5-l) 1 H- pyrazol-4-ll] - (5- isopropoxy-1 H-lndol-2-ll) - methanone
4141
55
1H-RMN (DMSOD6) 8: 12.46 (1H, s), 11.52 (1H, d, J = 1.8 Hz), 8.26 (1H, s), 7.65-7.55 (2H, br m), 7.36 (1H, d, J= 8.9 Hz), 7.32 (1H, d, J = 1.8 Hz), 7.29 (1H, dd, J = 8.5, 1.8 Hz), 7.13 (1H, d, J = 2.2 Hz), 6.98 (2H, br s), 6.89 (1H, dd, J =8.9, 2.2 Hz), 4.58-4.52 (1H, m), 2.53 (3H, s), 1.29 (6H, d, J = 6.1 Hz).1H-NMR (DMSOD6) 8: 12.46 (1H, s), 11.52 (1H, d, J = 1.8 Hz), 8.26 (1H, s), 7.65-7.55 (2H, br m), 7.36 (1H, d, J = 8.9 Hz), 7.32 (1H, d, J = 1.8 Hz), 7.29 (1H, dd, J = 8.5, 1.8 Hz), 7.13 (1H, d, J = 2.2 Hz), 6.98 (2H, br s ), 6.89 (1H, dd, J = 8.9, 2.2 Hz), 4.58-4.52 (1H, m), 2.53 (3H, s), 1.29 (6H, d, J = 6.1 Hz).
8181
[5-amino-1-(2-met¡l-1 H- bencim¡dazol-5-il)-1 H- plrazol-4-il] -[5-(2-metox¡- etoxi)-1 H-indol-2-il]- metanona[5-amino-1- (2-methyl-1 H- benzimdazol-5-yl) -1 H- plrazol-4-yl] - [5- (2-methoxy-ethoxy) -1 H -indol-2-il] - methanone
431431
8282
8383
V-CfVV-CfV
F OF O
[5-amlno-1-(2-metil-1 H- benclmldazol- 5-il)-1H- pirazol-4-il] -(5- ciclopropilmetoxi-1 H- ¡ndol-2 -il)-metanona[5-amlno-1- (2-methyl-1 H- benclmldazol- 5-yl) -1 H- pyrazol-4-yl] - (5- cyclopropylmethoxy-1 H- ndol-2-yl) -methanone
[5-amino-1-(2-metil-1 H- bencimidazol-5-¡l)-1 H- pirazol-4-il] -(2,2-difluoro- 5H-[1,3]dioxolo[4,5-f] indol-6-il)-metanona[5-amino-1- (2-methyl-1 H- benzimidazol-5-1) -1 H- pyrazol-4-yl] - (2,2-difluoro-5H- [1,3] dioxolo [4 , 5-f] indole-6-yl) -methanone
427427
437437
1H-RMN (DMSOD6) 8: 12.46 (1H, s), 11.56 (1H, d, J = 1.2 Hz), 8.27 (1H, s), 7.64-1.57 (2H, br m), 7.37 (1H, d, J = 9.1 Hz), 7.33 (1H, d, J = 1.2 Hz), 7.29 (1H, dd, J = 8.6, 1.8 Hz), 7.13 (1H, d, J = 2.4 Hz), 6.99 (2H, br s), 6.92 (1H, dd, J = 9.1, 2.4 Hz), 4.11-4.08 (2H, m), 3.70-3.68 (2H, m), 3.33 (3H, s), 2.53 (3H, s).1H-NMR (DMSOD6) 8: 12.46 (1H, s), 11.56 (1H, d, J = 1.2 Hz), 8.27 (1H, s), 7.64-1.57 (2H, br m), 7.37 (1H, d, J = 9.1 Hz), 7.33 (1H, d, J = 1.2 Hz), 7.29 (1H, dd, J = 8.6, 1.8 Hz), 7.13 (1H, d, J = 2.4 Hz), 6.99 (2H, br s ), 6.92 (1H, dd, J = 9.1, 2.4 Hz), 4.11-4.08 (2H, m), 3.70-3.68 (2H, m), 3.33 (3H, s), 2.53 (3H, s).
1H-RMN (DMSOD6) 8: 12.46 (1H, s), 11.54 (1H, s), 8.26 (1H, s), 7.65-7.55 (2H, br m), 7.36 (1H, d, J = 8.8 Hz), 7.31 (1H, s), 7.28 (1H, dd, J = 8.2, 2.2 Hz), 7.09 (1H, d, J = 2.5 Hz), 6.98 (2H, s), 6.92 (1H, dd, J = 8.8, 2.5 Hz), 3.82 (2H, d, J = 7.1 Hz), 2.53 (3H, s), 1.28-1H-NMR (DMSOD6) 8: 12.46 (1H, s), 11.54 (1H, s), 8.26 (1H, s), 7.65-7.55 (2H, br m), 7.36 (1H, d, J = 8.8 Hz) , 7.31 (1H, s), 7.28 (1H, dd, J = 8.2, 2.2 Hz), 7.09 (1H, d, J = 2.5 Hz), 6.98 (2H, s), 6.92 (1H, dd, J = 8.8 , 2.5 Hz), 3.82 (2H, d, J = 7.1 Hz), 2.53 (3H, s), 1.28-
I. 20 (1H, m), 0.60-0.56 (2H, m), 0.37- 0.31 (2H, m).I. 20 (1H, m), 0.60-0.56 (2H, m), 0.37-0.31 (2H, m).
1H-RMN (DMSOD6) 8: 12.46 (1H, s),1H-NMR (DMSOD6) 8: 12.46 (1H, s),
II. 96 (1H, s), 8.28 (1H, s), 7.65-7.55 (2H, br m), 7.60 (1H, s), 7.50 (1H, d, J = 1.9 Hz), 7.36 (1H, s), 7.28 (1H, dd, J = 8.5, 1.9 Hz), 7.07 (2H, br s), 2.53 (3H, s).II. 96 (1H, s), 8.28 (1H, s), 7.65-7.55 (2H, br m), 7.60 (1H, s), 7.50 (1H, d, J = 1.9 Hz), 7.36 (1H, s), 7.28 (1H, dd, J = 8.5, 1.9 Hz), 7.07 (2H, br s), 2.53 (3H, s).
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 84 84
- [5-amino-1-(2-metil-1H- bencimidazol-5-il)-1 H- pyazol-4-il] -[6-(3-cloro- piridin-2-il)-1 H-indol -2- il]-metanona 468, 470 1H-RMN (DMSOD6) 8: 12.48 (1H, s), 11.90 (1H, s), 8.86 (1H, dd, J = 4.7, 1.4 Hz), 8.36 (1H, s), 8.07 (1H, dd, J = 8.0, 1.4 Hz), 7.84 (1H, s), 7.79 (1H, d, J = 8.2 Hz), 7.64 (2H, s), 7.53 (1H, s), 7.46-7.41 (2H, m), 7.31 (1H, dd, J 8.5, 1.9 Hz), 7.05 (2H, s), 2.53 (3H, t, J = 5.5 Hz). [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 H- pyazol-4-yl] - [6- (3-chloro-pyridin-2-yl) -1 H-indole -2-yl] -methanone 468, 470 1H-NMR (DMSOD6) 8: 12.48 (1H, s), 11.90 (1H, s), 8.86 (1H, dd, J = 4.7, 1.4 Hz), 8.36 (1H, s), 8.07 (1H, dd, J = 8.0, 1.4 Hz), 7.84 (1H, s), 7.79 (1H, d, J = 8.2 Hz), 7.64 (2H, s), 7.53 (1H, s), 7.46-7.41 (2H, m), 7.31 (1H, dd, J 8.5, 1.9 Hz), 7.05 (2H, s), 2.53 (3H, t, J = 5.5 Hz).
- 85 85
- M [5-amino-1-(2-metil-1H- bencimidazol-5-il)-1 H- pirazol-4-il]-[6-(5-fluoro- piridin-2-il)-1 H-indol -2- il]-metanona 452 1H-RMN (DMSOD6) 8: 12.48 (1H, s), 11.92 (1H, s), 8.68 (1H, d, J = 2.7 Hz), 8.35 (1H, s), 8.21 (1H, d, J = 1.1 Hz), 8.05 (1H, dd, J = 8.8, 4.4 Hz), 7.85-7.79 (3H, m), 7.63 (2H, s). 7.50 (1H, s), 7.31 (1 H, dd, J = 8.5, 1.9 Hz), 7.05 (2H, s), 2.56 (3H, s). M [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 H- pyrazol-4-yl] - [6- (5-fluoro-pyridin-2-yl) -1 H- indole -2-yl] -methanone 452 1H-NMR (DMSOD6) 8: 12.48 (1H, s), 11.92 (1H, s), 8.68 (1H, d, J = 2.7 Hz), 8.35 (1H, s), 8.21 (1H, d, J = 1.1 Hz), 8.05 (1H, dd, J = 8.8, 4.4 Hz), 7.85-7.79 (3H, m), 7.63 (2H, s). 7.50 (1H, s), 7.31 (1 H, dd, J = 8.5, 1.9 Hz), 7.05 (2H, s), 2.56 (3H, s).
- 86 86
- í^1 'rxCÓ-Lr [5-amino-1-(2-metil-I Hbencimidazol-5-il)-1 H- pirazol-4-il] -[6-(6- morfolin-4-il-piridazi n-3- il)-1 H-indol-2-il]- metanona 520 1H-RMN (DMSOD6) 8: 12.47 (1H, d, J = 5.5 Hz), 11.90 (1H, d, J = 2.2 Hz), 8.34 (1H, d, J = 4.9 Hz). 8.17 (1H, s), 7.98 (1H, d, J = 9.3 Hz), 7.82-7.74 (2H, m), 7.68-7.64 (1H, m), 7.60-7.55 (1H, m), 7.50 (1H, s), 7.38 (1H, d, J = 9.3Hz), 7.33-7.28 (1H, m), 7.07(1 H, s), 7.01(1H, s), 3.80-3.74 (4H, m), 3.65-3.60 (4H, m), 2.53 (3H, s). í ^ 1 'rxCÓ-Lr [5-amino-1- (2-methyl-I Hbenzimidazol-5-yl) -1 H- pyrazol-4-yl] - [6- (6- morpholin-4-yl-pyridazi n-3- il) -1 H-indole-2-yl] - methanone 520 1H-NMR (DMSOD6) 8: 12.47 (1H, d, J = 5.5 Hz), 11.90 (1H, d, J = 2.2 Hz) , 8.34 (1H, d, J = 4.9 Hz). 8.17 (1H, s), 7.98 (1H, d, J = 9.3 Hz), 7.82-7.74 (2H, m), 7.68-7.64 (1H, m), 7.60-7.55 (1H, m), 7.50 (1H, s), 7.38 (1H, d, J = 9.3Hz), 7.33-7.28 (1H, m), 7.07 (1 H, s), 7.01 (1H, s), 3.80-3.74 (4H, m), 3.65- 3.60 (4H, m), 2.53 (3H, s).
- 87 87
- W*fM' ^ t¡ [5-amino-1-(2-metil-1H- bencimidazol-5-il)-1 H- pirazol-4-il] -(5-cloro-6- ciclopropilmetoxi-1H - indol-2-il)-metanona 461,463 1H-MMR (DMSOD6) 8: 12.45 (1H, s), 11.66 (1H, s), 8.25 (1H, 1H-RMN (DMSO-D6) 8: 12.45 (1H, s), 11.66 (1H, s), 7.72 (1H, s), 7.62-7.58 (2H, m), 7.37 (1H, d, J = 1.3 Hz), 7.28 (1H, dd, J = 8.2, 1.3 Hz), 7.02 (1H, s), 6.97 (2H, s), 3.92 (2H, d, J = 7.1 Hz), 2.53 (3H, s), 1.35-1.25 (1H, m), 0.64-0.59 (2H, m), 0.44-0.39 (2H, m). W * fM '^ t¡ [5-amino-1- (2-methyl-1H- benzimidazol-5-yl) -1 H- pyrazol-4-yl] - (5-chloro-6- cyclopropylmethoxy-1H - indole -2-yl) -methanone 461,463 1H-MMR (DMSOD6) 8: 12.45 (1H, s), 11.66 (1H, s), 8.25 (1H, 1H-NMR (DMSO-D6) 8: 12.45 (1H, s) , 11.66 (1H, s), 7.72 (1H, s), 7.62-7.58 (2H, m), 7.37 (1H, d, J = 1.3 Hz), 7.28 (1H, dd, J = 8.2, 1.3 Hz), 7.02 (1H, s), 6.97 (2H, s), 3.92 (2H, d, J = 7.1 Hz), 2.53 (3H, s), 1.35-1.25 (1H, m), 0.64-0.59 (2H, m) , 0.44-0.39 (2H, m).
- 88 88
- Tl3>tw».- ^"■O-r [5-amino-1-(2-metil-1H- bencimidazol- 5-il)-1H- pirazol-4-il] -[6-(2,4- difluoro-fenil)-1 H-indol-2 -il]-metanona 469 1H-RMN (DMSOD6) 8: 12.51 (1H, s), 11.88 (1H, s), 8.35 (1H, s), 7.79 (1H, d, J = 7.7 Hz), 7.62 (4H, s), 7.52 (1H, s), 7.46-7.16 (4H, m), 7.05 (2H, s), 2.54 (3H, s). Tl3> tw ».- ^" ■ Or [5-amino-1- (2-methyl-1H- benzimidazol- 5-yl) -1H- pyrazol-4-yl] - [6- (2,4- difluoro- phenyl) -1 H-indole-2-yl] -methanone 469 1H-NMR (DMSOD6) 8: 12.51 (1H, s), 11.88 (1H, s), 8.35 (1H, s), 7.79 (1H, d, J = 7.7 Hz), 7.62 (4H, s), 7.52 (1H, s), 7.46-7.16 (4H, m), 7.05 (2H, s), 2.54 (3H, s).
- 89 89
- [5-amino-1-(2-metil-1H- bencimidazol-5-il)-1 H- pirazol-4-il] -(6-piridazin- 4-il-11 H-indol-2-il)- metanona 435 1H-RMN (DMSOD6) 8: 12.48 (1H, s), 12.04 (1H, s), 9.67 - 9.64 (1H, m), 9.27 (1H, d, J = 5.5 Hz), 8.35 (1H, d, J = 4.4 Hz), 8.02 (1H, dd, J = 5.5, 2.7 Hz). 7.95 (1H, s), 7.89 (1 H, d, J = 8.8 Hz), 7.67-7.55 (4H, m), 7.30 (1H, J = 6.3 Hz), 7.10 (1H, s), 7.04 (1H, s), 2.54 (3H, s). [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 H- pyrazol-4-yl] - (6-pyridazin-4-yl-11 H-indole-2-yl) - methanone 435 1H-NMR (DMSOD6) 8: 12.48 (1H, s), 12.04 (1H, s), 9.67-9.64 (1H, m), 9.27 (1H, d, J = 5.5 Hz), 8.35 (1H, d , J = 4.4 Hz), 8.02 (1H, dd, J = 5.5, 2.7 Hz). 7.95 (1H, s), 7.89 (1 H, d, J = 8.8 Hz), 7.67-7.55 (4H, m), 7.30 (1H, J = 6.3 Hz), 7.10 (1H, s), 7.04 (1H, s), 2.54 (3H, s).
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 204 204
- tt—f ys <=¿ w [5-amino-1-(2-metil- 3Hbencimidazol-5-il)-1 H- pirazol-4-il]-(6-cloro-1 H- indol-2-il)-metanona 391 11.8 (1H, brs), 8.28 (1H, m), 7.707.68 (1H, m), 7.60 (2H, m), 7.46 (2H, m), 7.29-7.27 (1H, m), 7.01 (2H, m), 2.52 (3H, s) tt — f ys <= ¿w [5-amino-1- (2-methyl- 3Hbenzimidazol-5-yl) -1 H- pyrazol-4-yl] - (6-chloro-1 H- indole-2-yl ) -methanone 391 11.8 (1H, brs), 8.28 (1H, m), 7,707.68 (1H, m), 7.60 (2H, m), 7.46 (2H, m), 7.29-7.27 (1H, m), 7.01 (2H, m), 2.52 (3H, s)
- 205 205
- H o [5-amino-1-(2-metil-1 H- bencimidazol-5-il)-1 H- pirazol-4-il]-(5-cloro-1 H- indol-2-il)-metanona 391 11.91 (s, 1H), 8.30 (s, 1H), 7.71 (m, 3H), 7.45 (m, 4H), 7.26 (m, 1H), 7.09 (s, 2H), 2.62 (s, 3H). H or [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 H- pyrazol-4-yl] - (5-chloro-1 H- indole-2-yl) -methanone 391 11.91 (s, 1H), 8.30 (s, 1H), 7.71 (m, 3H), 7.45 (m, 4H), 7.26 (m, 1H), 7.09 (s, 2H), 2.62 (s, 3H).
- 206 206
- [5-amino-1-(2-metil-1 H- bencimidazol-5-il)-1 H- pirazol-4-il]-(1 H-indol-3-il)- metanona 357 11.92 (s, 1H), 8.32 (m, 1H), 8.25 (d, J= 7.6 Hz, 1H), 8.20 (s, 1H), 7.77 (m, 2H), 7.51 (m, 2H), 7.18 (m, 2H), 6.97 (s, 2H), 2.67 (s, 3H). [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 H- pyrazol-4-yl] - (1 H-indol-3-yl) - methanone 357 11.92 (s, 1H ), 8.32 (m, 1H), 8.25 (d, J = 7.6 Hz, 1H), 8.20 (s, 1H), 7.77 (m, 2H), 7.51 (m, 2H), 7.18 (m, 2H), 6.97 (s, 2H), 2.67 (s, 3H).
- 207 207
- H [5-amino-1-(2-metil-1 H- bencimidazol- 5-il)-1H- pirazol-4-il]-(1 H-indol-6-il)- metanona 357 12.42 (s, 1H), 11.36 (s, 1H), 7.91 (s, 1H), 7.85 (m,1H), 7.66 (d, J= 8.3 Hz, 1H), 7.58 (m, 3H), 7.48 (d, J= 8 Hz, 1H), 7.29 (d, J= 8.7 Hz, 1H), 6.95 (br s, 2H), 6.54 (s, 1H), 2.53 (s, 3H). H [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 H- pyrazol-4-yl] - (1 H-indol-6-yl) - methanone 357 12.42 (s, 1H ), 11.36 (s, 1H), 7.91 (s, 1H), 7.85 (m, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.58 (m, 3H), 7.48 (d, J = 8 Hz , 1H), 7.29 (d, J = 8.7 Hz, 1H), 6.95 (br s, 2H), 6.54 (s, 1H), 2.53 (s, 3H).
- 208 208
- FyV-N 0 ^"t^T H [5-amino-1-(2-metil-1 H- bencimidazol-5-il)-1 H- pirazol-4-il]-(5-bromo-6- fluoro-1 H-indol-2-il)- metanona 453 12.48 9 (s, 1H), 11.97 (s, 1H), 8.27 (s, 1H), 8.01 (d, J= 7 Hz, 1H), 7.62 (m, 2H), 7.36 (d, J= 9.6 Hz, 1H), 7.29 (d, J= 7.6 Hz, 1H), 7.02 (br s, 2H). 2.54 (s,3H) FyV-N 0 ^ "t ^ TH [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 H- pyrazol-4-yl] - (5-bromo-6- fluoro- 1 H-indole-2-yl) - methanone 453 12.48 9 (s, 1H), 11.97 (s, 1H), 8.27 (s, 1H), 8.01 (d, J = 7 Hz, 1H), 7.62 (m, 2H), 7.36 (d, J = 9.6 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.02 (br s, 2H). 2.54 (s, 3H)
- 209 209
- ^0^“= *Nt^Cr [5-amino-1-(2-etil-1H- bencimidazol-5-il)-1 H- pirazol-4-il]-(5-bromo-6- fluoro-1 H-indol-2-il)- metanona 467 12.48 (s, 1H), 11.98 (s, 1H), 8.27(d, J= 4.5 Hz, 1H), 8.01 (d, J= 6.8 Hz, 1H), 7.67 (m, 1H), 7.57 (s, 1H). 7.46 (s, 1H), 7.37 (d, J= 9.4 Hz, 1H), 7.29 (t, J= 7.7 Hz, 1H), 7.03 (m, 2H), 2.86 (m, 2H), 1.34 (m,3H) ^ 0 ^ "= * Nt ^ Cr [5-amino-1- (2-ethyl-1H- benzimidazol-5-yl) -1 H- pyrazol-4-yl] - (5-bromo-6- fluoro-1 H-indole-2-yl) - methanone 467 12.48 (s, 1H), 11.98 (s, 1H), 8.27 (d, J = 4.5 Hz, 1H), 8.01 (d, J = 6.8 Hz, 1H), 7.67 (m, 1H), 7.57 (s, 1H). 7.46 (s, 1H), 7.37 (d, J = 9.4 Hz, 1H), 7.29 (t, J = 7.7 Hz, 1H), 7.03 (m, 2H), 2.86 (m, 2H), 1.34 (m, 3H )
- 210 210
- ;src¿-^- ' "‘üCr h [5-amino-1-(2-metil-1 H- bencimidazol-5-il)-1 H- pirazol-4-il]-(5-trifluorometil- 1 H-indol-2-il)-metanona 425 12.15 (s, 1H), 8.33 (s, 1H), 8.10 (s, 1H), 7.74 (m, 2H), 7.67 (d, J= 8.5 Hz, 1H), 7.62 (s, 1H), 7.54 (d, J= 8.5 Hz, 1H), 7.45 (d, J= 8.6 Hz, 1H), 7.13 (m, 2H), 2.65 (s, 3H) ; src¿ - ^ - '"' üCr h [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 H- pyrazol-4-yl] - (5-trifluoromethyl- 1 H -indole-2-yl) -methanone 425 12.15 (s, 1H), 8.33 (s, 1H), 8.10 (s, 1H), 7.74 (m, 2H), 7.67 (d, J = 8.5 Hz, 1H), 7.62 (s, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.45 (d, J = 8.6 Hz, 1H), 7.13 (m, 2H), 2.65 (s, 3H)
- 211 211
- ti &£sHr- vxír H [5-amino-1-(2-metil-1 H- bencimidazol- 5-il)-1H- pirazol-4-il]-(5- trifluorometoxi-1H-indol- 2- il)-metanona 441 12.48 (s, 1H), 11.99 (s, 1H), 8.29 (d, J= 4.8 Hz, 1H), 7.66 (d, J= 8.6 Hz, 2H), 7.56 (d, J= 9.3 Hz, 1H), 7.52 (s, 2H), 7.27 (m, 2H), 7.16 (m, 1H), 7.05 (m, 2H), 2.53 (s, 3H) ti & £ sHr- vxír H [5-amino-1- (2-methyl-1 H- benzimidazol- 5-yl) -1H- pyrazol-4-yl] - (5- trifluoromethoxy-1H-indole- 2- il ) -methanone 441 12.48 (s, 1H), 11.99 (s, 1H), 8.29 (d, J = 4.8 Hz, 1H), 7.66 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 9.3 Hz , 1H), 7.52 (s, 2H), 7.27 (m, 2H), 7.16 (m, 1H), 7.05 (m, 2H), 2.53 (s, 3H)
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 212 212
- c, v^V H [5-amino-1-(2-metil-1 H- bencimidazol- 5-¡l)-1H- plrazol-4-¡l]-(4,6-dicloro-1 H- ¡ndol-2-il)-metanona 425 12.47 (s, 1H), 12.21 (s, 1H), 8.33 (d, J= 5.6 Hz, 1H), 7.95 (brs, 1H), 7.65 (d, J= 7.8 Hz, 1H), 7.56 (d, J= 6.9 Hz, 1H), 7.48 (s, 1H), 7.37 (s, 1H), 7.28 (m, 1H), 7.22 (m, 1H), 7.09 (s, 1H), 7.03 (s, 1H), 2.53 (s, H) c, v ^ VH [5-amino-1- (2-methyl-1 H- benzimidazol-5-¡1) -1 H- plrazol-4-¡1] - (4,6-dichloro-1 H- ndol -2-yl) -methanone 425 12.47 (s, 1H), 12.21 (s, 1H), 8.33 (d, J = 5.6 Hz, 1H), 7.95 (brs, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 6.9 Hz, 1H), 7.48 (s, 1H), 7.37 (s, 1H), 7.28 (m, 1H), 7.22 (m, 1H), 7.09 (s, 1H), 7.03 (s, 1H), 2.53 (s, H)
- 213 213
- i ÍW', [5-amino-1-(2-metil-1 H- bencimidazol- 5-¡l)-1H- pirazol-4- il]-(6-bromo-4- fluoro-1 H-indol-2-il)- metanona 453 12.16 (s, 1H), 8.38 (s, 1H), 7.65 (m, 2H), 7.50 (d, J= 5.3 Hz, 2H), 7.34 (m, 1H), 7.13(m, 1H), 7.09 (m, 2H), 2.57 (s, 3H) i ÍW ', [5-amino-1- (2-methyl-1 H- benzimidazol-5-l) -1H- pyrazol-4- yl] - (6-bromo-4- fluoro-1 H-indole- 2-yl) - methanone 453 12.16 (s, 1H), 8.38 (s, 1H), 7.65 (m, 2H), 7.50 (d, J = 5.3 Hz, 2H), 7.34 (m, 1H), 7.13 (m , 1H), 7.09 (m, 2H), 2.57 (s, 3H)
- 214 214
- FfF 0'r^'i'ÍÍ. o VX'C- H [5-amino-1-(2-met¡l-1 H- bencimidazol- 5-¡l)-1H- pirazol-4-il]-(6- trifluorometox¡-1H-¡ndol- 2- ilj-metanona 441 12.5 (s, 1H), 11.93 (s, 1H), 8.31 (s, 1H), 7.80 (d, J =8.7 Hz, 1H), 7.62 (s, 2H), 7.53 (s, 1H), 7.41 (s, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7.20 (m, 1H), 7.06 (m, 3H), 2.53 (s, 3H). FfF 0'r ^ 'i'ÍÍ. or VX'C- H [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 H- pyrazol-4-yl] - (6- trifluoromethoxy-1H-landol - 2- ilj-methanone 441 12.5 (s, 1H), 11.93 (s, 1H), 8.31 (s, 1H), 7.80 (d, J = 8.7 Hz, 1H), 7.62 (s, 2H), 7.53 (s , 1H), 7.41 (s, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7.20 (m, 1H), 7.06 (m, 3H), 2.53 (s, 3H).
- 215 215
- [5-amino-1-(2-etll-1H- bencim¡dazol-5-¡l)-1 H- pirazol-4-il]-(5- trifluorometoxi-1 H-indol- 2- ilj-metanona 455 12.50 (s, 1H), 11.98 (s, 1H), 8.29 (s, 1H), 7.67 (s, 1H), 7.63 (br s, 1H), 7.57 (d, J= 8.9 Hz, 1H), 7.51 (m, 1H), 7.29 (d, J= 8.3 Hz, 1H), 7.23 (d, J= 8.4 Hz, 1H), 7.04 (s, 1H), 2.87 (m,2H), 1.48 (m, 3H) [5-amino-1- (2-etll-1H- benzimdadazol-5-l) -1 H- pyrazol-4-yl] - (5- trifluoromethoxy-1 H-indole-2-yl-methanone 455 12.50 (s, 1H), 11.98 (s, 1H), 8.29 (s, 1H), 7.67 (s, 1H), 7.63 (br s, 1H), 7.57 (d, J = 8.9 Hz, 1H), 7.51 ( m, 1H), 7.29 (d, J = 8.3 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.04 (s, 1H), 2.87 (m, 2H), 1.48 (m, 3H)
- 216 216
- h ^YXV-v ^■'ka [5-amino-1-(2-et¡l-1H- bencimidazol- 5-¡l)-1H- pirazol-4-il]-(5-tr¡fluoromet¡l- 1 H-¡ndol-2-¡l)-metanona 439 12.16 (s, 1H), 8.33 (brs, 1H), 8.10 (brs, 1H), 7.73 (m, 2H), 7.67(d, J= 8.2 Hz, 1H), 7.62 (s, 1H), 7.54 (d, J= 8.3 Hz, 1H), 7.43 (m, 1H), 7.12 (brs, 3H), 2.96 (m, 2H), 1.37 (m, 3H) h ^ YXV-v ^ ■ 'ka [5-amino-1- (2-et¡l-1H- benzimidazol- 5-¡) -1H- pyrazol-4-yl] - (5-trfluoromet¡l - 1 H-¡ndol-2-¡l) -methanone 439 12.16 (s, 1H), 8.33 (brs, 1H), 8.10 (brs, 1H), 7.73 (m, 2H), 7.67 (d, J = 8.2 Hz, 1H), 7.62 (s, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.43 (m, 1H), 7.12 (brs, 3H), 2.96 (m, 2H), 1.37 (m, 3H )
- 217 217
- «WV" i3 «X^-í,*1 [5-amino-1-(2-metil-1 H- bencimidazol- 5-¡l)-1 H- pirazol-4-il]-(5,6-d¡cloro-1 H- ¡ndol-2-il)-metanona 425 11.98 (s, 1H), 8.30 (s, 1H), 7.96 (s, 1H), 7.70 (m, 3H), 7.46 (s, 1H), 7.42 (d, J= 8.8 Hz, 1H), 7.11 (s, 2H), 2.67 (s, 3H) «WV" i3 «X ^ -í, * 1 [5-amino-1- (2-methyl-1 H- benzimidazol-5-l) -1 H- pyrazol-4-yl] - (5,6- dichloro-1 H- ndol-2-yl) -methanone 425 11.98 (s, 1H), 8.30 (s, 1H), 7.96 (s, 1H), 7.70 (m, 3H), 7.46 (s, 1H ), 7.42 (d, J = 8.8 Hz, 1H), 7.11 (s, 2H), 2.67 (s, 3H)
- 218 218
- ■x&v V^-.. M [5-amino-1-(2-et¡l-1H- bencimidazol-5-¡l)-1 H- p¡razol-4-il]-(6-bromo-5- fluoro-1 H-¡ndol-2-M)- metanona 467 11.91 (s, 1H), 8.28 (s, 1H), 7.74 (d, J= 6 Hz, 1H), 7.64 (d, J= 9 Hz, 3H), 7.46 (s, 1H), 7.31 (d, J= 7.8 Hz, 1H), 7.06 (br s, 2H), 2.89 (q, J= 7.2 Hz, 2H), 1.35 (t, J= 7.2 Hz, 3H). ■ x & v V ^ - .. M [5-amino-1- (2-et¡l-1H- benzimidazol-5-¡l) -1 H- p¡razol-4-yl] - (6-bromo-5 - fluoro-1 H-¡ndol-2-M) - methanone 467 11.91 (s, 1H), 8.28 (s, 1H), 7.74 (d, J = 6 Hz, 1H), 7.64 (d, J = 9 Hz , 3H), 7.46 (s, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.06 (br s, 2H), 2.89 (q, J = 7.2 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H).
- 219 219
- 11 [5-am¡no-1-(2-metil-1H- bencimidazol- 5-¡l)-1H- pirazol-4-il]-(4,5-d¡cloro-1 H- ¡ndol-2-il)-metanona 425 12.46 (s, 2H), 7.66 (m, 1H), 7.57 (d, J= 7.6 Hz, 1H), 7.49 (m, 1H), 7.43 (d, J= 8.7 Hz, 1H), 7.30 (t, J= 6.6 Hz, 1H), 7.05 (m, 2H), 2.53 (s, 3H) 11 [5-am-1-1 (2-methyl-1 H- benzimidazol-5-1) -1 H- pyrazol-4-yl] - (4,5-dichloro-1 H- ndol-2 -il) -methanone 425 12.46 (s, 2H), 7.66 (m, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.49 (m, 1H), 7.43 (d, J = 8.7 Hz, 1H) , 7.30 (t, J = 6.6 Hz, 1H), 7.05 (m, 2H), 2.53 (s, 3H)
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 220 220
- ' V~-Y^rV H [5-amino-1-(2-metil-1H- bencimidazol-5-il)-1 H- pirazol-4-il]-(4,6-difluoro- 1 H-indol-2-il)-metanona 393 12.40 (m, 1H), 12.12 (s, 1H), 8.37 (s, 1H), 7.62 (s, 2H), 7.49 (s, 1H), 7.29 (m, 1H), 7.07 (m, 3H), 6.94 (m, 1H), 2.54 (s, 3H). 'V ~ -Y ^ rV H [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 H- pyrazol-4-yl] - (4,6-difluoro- 1 H-indole -2-yl) -methanone 393 12.40 (m, 1H), 12.12 (s, 1H), 8.37 (s, 1H), 7.62 (s, 2H), 7.49 (s, 1H), 7.29 (m, 1H), 7.07 (m, 3H), 6.94 (m, 1H), 2.54 (s, 3H).
- 221 221
- «"Y1 H xrH,- S.-"Y'VV' [5-amino-1-(2-metil-1H- bencimidazol- 5-il)-1H- pi razol-4-il]-[6-(3-cloro- piridin-4-il)-1 H-indol-2-il]- metanona 468 11.95 (bs, 1H), 8.75 (s, 1H), 8.59 (d, 1H, J = 4 Hz), 8.41 (bs, 1H), 7.95 (m, 1H), 7.89 (m, O), 7.82 (d, 1H, J = 12 Hz), 7.66 (m, 1H), 7.64 (m, 1H), 7.54 (m, 2H), 7.22 (m, 2H), 6.86 (s, 1H), 6.63 (s, 1H), 2.8 (s, 3H), 2.18 (s, 3H) «" Y1 H xrH, - S .- "Y'VV '[5-amino-1- (2-methyl-1H- benzimidazol- 5-yl) -1H- pi razol-4-yl] - [6- ( 3-Chloro-pyridin-4-yl) -1 H-indol-2-yl] - methanone 468 11.95 (bs, 1H), 8.75 (s, 1H), 8.59 (d, 1H, J = 4 Hz), 8.41 (bs, 1H), 7.95 (m, 1H), 7.89 (m, O), 7.82 (d, 1H, J = 12 Hz), 7.66 (m, 1H), 7.64 (m, 1H), 7.54 (m, 2H), 7.22 (m, 2H), 6.86 (s, 1H), 6.63 (s, 1H), 2.8 (s, 3H), 2.18 (s, 3H)
- 222 222
- ^XXHr ^'ÍXV- ^ H [5-amino-1-(2-metil-1H- bencimidazol- 5-il)-1H- pirazol-4-il]-[6-(6-metil- piridina-3-il)-1 H-indol- 2-il]- metanona 448 8.73 (1H, m), 8.30 (1H, m), 8.078.04 (1H, m), 7.86-7.84 (2H, m), 7.75 (1H, m), 7.68 (2H, m), 7.427.39 (4H, m), 2.62 (3H, s), 2.59 (3H, s) ^ XXHr ^ 'ÍXV- ^ H [5-amino-1- (2-methyl-1H- benzimidazol-5-yl) -1H- pyrazol-4-yl] - [6- (6-methyl-pyridine-3- il) -1 H-indole-2-yl] - methanone 448 8.73 (1H, m), 8.30 (1H, m), 8.078.04 (1H, m), 7.86-7.84 (2H, m), 7.75 (1H , m), 7.68 (2H, m), 7.427.39 (4H, m), 2.62 (3H, s), 2.59 (3H, s)
- 223 223
- r 1^ o V'VV'1— [5-amino-1-(2-metil-1H- bencimidazol- 5-il)-1H- pi razol-4-il]-[6-(5-fluoro- piridin-3-il)-1 H-indol- 2-il]- metanona 452 11.95 (s, 1H), 8.009 (m, 1H), 7.80 (m, 2H), 7.70 (m, 1H), 7.54 (m, 2H), 7.38 (d, 1H, J = 12 Hz), 7.17 (bs, 1H), 2.85 (s, 1H), 2.65 (m, 1H), 2.55 (s, 3H) r 1 ^ or V'VV'1— [5-amino-1- (2-methyl-1H- benzimidazol- 5-yl) -1H- pi razol-4-yl] - [6- (5-fluoro-pyridin -3-yl) -1 H-indole-2-yl] - methanone 452 11.95 (s, 1H), 8.009 (m, 1H), 7.80 (m, 2H), 7.70 (m, 1H), 7.54 (m, 2H), 7.38 (d, 1H, J = 12 Hz), 7.17 (bs, 1H), 2.85 (s, 1H), 2.65 (m, 1H), 2.55 (s, 3H)
- 224 224
- _/-íV ■H^-F rf [5-amino-1-(2-metil-1H- bencimidazol-5-il)-1 H- pirazol-4-il]-[6-(2- trifluorometil-piridin-3-il)- 1 H-indol-2-il]-metanona 502 8.30 (s, 2H), 8.17 (m, 1H), 8.06 (t, 1H, J = 8 Hz), 7.86 (q, 2H, J = 12 Hz), 7.67 (d, 3H, J = 8 Hz), 7.40 (m, 2 H), 2.61 (m, 3H), _ / - íV ■ H ^ -F rf [5-amino-1- (2-methyl-1H- benzimidazol-5-yl) -1 H- pyrazol-4-yl] - [6- (2- trifluoromethyl-pyridin -3-yl) - 1 H-indole-2-yl] -methanone 502 8.30 (s, 2H), 8.17 (m, 1H), 8.06 (t, 1H, J = 8 Hz), 7.86 (q, 2H, J = 12 Hz), 7.67 (d, 3H, J = 8 Hz), 7.40 (m, 2 H), 2.61 (m, 3H),
- 225 225
- □ -_ L, J fHpJxr^ [5-amino-1-(2-metil-1H- bencimidazol-5-il)-1 H- pi razol-4-il]-[6-(5-cloro-2- metoxipiridin- 3-il)-1H- indol-2-il]-metanona 498 8.30 (1H, s), 8.09 (1H, d, J = 2.8 Hz), 7.78 (2H, m), 7.69 (3H, m), 7.42 (2H, m), 7.28 (1H, m), 5.78 (2H, m), 3.96 (3H, s), 2.63 (3H, s), 2.02 (3H, m) □ -_ L, J fHpJxr ^ [5-amino-1- (2-methyl-1H- benzimidazol-5-yl) -1 H- pi razol-4-yl] - [6- (5-chloro-2- methoxypyridin-3-yl) -1H- indole-2-yl] -methanone 498 8.30 (1H, s), 8.09 (1H, d, J = 2.8 Hz), 7.78 (2H, m), 7.69 (3H, m) , 7.42 (2H, m), 7.28 (1H, m), 5.78 (2H, m), 3.96 (3H, s), 2.63 (3H, s), 2.02 (3H, m)
- 226 226
- A vK^W- ^■-s [5-amino-1-(2-metil-1H- bencimidazol-5-il)-1 H- pi razol-4-il]-[6-(5-cloro- piridin-3-il)-1 H-indol- 2-il]- metanona 468 12.55 (bs, 1H), 11.95 (bs, 1H), 8.87 (m, 1H), 8.62 (d, 1H, J = 2.4 Hz), 8.34 (s, 1H), 8.23 (t, 1H, J = 2 Hz), 7.82 (d, 1H, J = 8 Hz), 7.78 (s, 1H), 7.60 (m, 3H), 7.52 (m, 1 H), 7.47(d, 1H, J=8 Hz), 7.28 (m, 1 H), 7.05 (m, 1H), 2.54 (s, 3 H) A vK ^ W- ^ ■ -s [5-amino-1- (2-methyl-1H- benzimidazol-5-yl) -1 H- pi razol-4-yl] - [6- (5-chloro-pyridin -3-yl) -1 H-indole-2-yl] - methanone 468 12.55 (bs, 1H), 11.95 (bs, 1H), 8.87 (m, 1H), 8.62 (d, 1H, J = 2.4 Hz) , 8.34 (s, 1H), 8.23 (t, 1H, J = 2 Hz), 7.82 (d, 1H, J = 8 Hz), 7.78 (s, 1H), 7.60 (m, 3H), 7.52 (m, 1 H), 7.47 (d, 1H, J = 8 Hz), 7.28 (m, 1 H), 7.05 (m, 1H), 2.54 (s, 3 H)
- 227 227
- .-A -A-J! ^ *-?-Oj Q-O-i [5-amino-1-(2-metil-1H- bencimidazol- 5-il)-1H- pi razol-4-il]-(6-ti ofen-3-il- 1 H-indol-2-il)-metanona 439 12.55 (bs, 1H), 11.74 (s, 1H), 8.32 (s, 1H), 7.82 (m, 1H), 7.71 (m, 2H), 7.66 (m, 1H), 7.60 (m, 2H), 7.54 (d, 1H, J = 4 Hz), 7.3 (m, 1H), 2.54 (s, 3H) .-A -A-J! ^ * -? - Oj QOi [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 H- pi razol-4-yl] - (6-ti ofen-3-yl- 1 H -indole-2-yl) -methanone 439 12.55 (bs, 1H), 11.74 (s, 1H), 8.32 (s, 1H), 7.82 (m, 1H), 7.71 (m, 2H), 7.66 (m, 1H ), 7.60 (m, 2H), 7.54 (d, 1H, J = 4 Hz), 7.3 (m, 1H), 2.54 (s, 3H)
EjemploExample
EstructuraStructure
Nombre del compuestoCompound Name
228228
229229
230230
231231
232232
233233
2342. 3. 4
N'NXXrN'NXXr
[5-amino-1-(2-metil-1 H- bencimidazol-5-il)-1 H- pirazol-4-¡l]-[6-(4- cloropl ridi n-3-il)-1 H-indol- 2-¡l]-metanona[5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 H- pyrazol-4-α] - [6- (4- chloropl ridi n-3-yl) -1 H -indole- 2-¡l] -methanone
468468
11.87 (s, 1H), 8.61 (m, 2 H), 8.51 (m, 2 H), 8.36 (bs, 1H), 7.78 (m, 3H), 7.66 (m, 1H), 7.51 (m, 3 H), 7.15 (m, 3 H), 3.04 (s, 2 H), 2.68 (s, 3 H),1.47(bs,1 H), 1.16 (m, 6 H)11.87 (s, 1H), 8.61 (m, 2 H), 8.51 (m, 2 H), 8.36 (bs, 1H), 7.78 (m, 3H), 7.66 (m, 1H), 7.51 (m, 3 H ), 7.15 (m, 3 H), 3.04 (s, 2 H), 2.68 (s, 3 H), 1.47 (bs, 1 H), 1.16 (m, 6 H)
[5-am¡no-1-(2-met¡l-1 H- benc¡m¡dazol-5-¡l)-1 H- pi razol-4-M]-(6-t¡ofen-2-il- 1 H-¡ndol-2-il)-metanona[5-am-1-1 (2-methyl-1 H- benzyldazol-5-l) -1 H- pi razol-4-M] - (6-tofen-2 -il- 1 H-¡ndol-2-il) -methanone
439439
11.75 (s, 1H), 8.35 (s, 1H), 7.75 (m, 4H), 7.48 (m, 5H), 7.14 (m, 3H), 3.08 (s, 1H), 2.65 (s, 3H),11.75 (s, 1H), 8.35 (s, 1H), 7.75 (m, 4H), 7.48 (m, 5H), 7.14 (m, 3H), 3.08 (s, 1H), 2.65 (s, 3H),
•O i-• OR i-
* f* f
H.H.
* F* F
va-goes-
r V1'£x>r V1 '£ x>
r i ■' ¡r i ■ '¡
C ' oC 'o
...r... r
[5-amino-1-(2-metil-1 H- bencimidazol-5-il)-1 H- pirazol-4-¡l]-[6-(3-fluoro- p¡r¡d¡n-4-il)-1 H-indol- 2-¡l]- metanona[5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 H- pyrazol-4-¡] - [6- (3-fluoro-p¡r¡d¡n-4 -il) -1 H-indole- 2-¡] - methanone
452452
12.59 (s, 1H), 11.96 (s, 1H), 8.66 (d, 1H, J = 8 Hz), 8.51 (d, 1H, J = 4 Hz), 8.34 (m, 1H), 7.84 (d, 2H), 7.81 (s, 1H), 7.67 (m, 2H), 7.56 (m, 2H), 7.29 (m, 1H), 7.02(m,2H), 2.67(3, 3H)12.59 (s, 1H), 11.96 (s, 1H), 8.66 (d, 1H, J = 8 Hz), 8.51 (d, 1H, J = 4 Hz), 8.34 (m, 1H), 7.84 (d, 2H ), 7.81 (s, 1H), 7.67 (m, 2H), 7.56 (m, 2H), 7.29 (m, 1H), 7.02 (m, 2H), 2.67 (3, 3H)
[5-am¡no-1-(2-met¡l-1 H- benc¡midazol-5-¡l)-1 H- pirazol-4-il]-16-(2- trifluorometil-pmdin-4-il)- 1 H-indol-2-ill-metanona[5-am-1-1 (2-methyl-1 H- benzimidazol-5-1) -1 H- pyrazol-4-yl] -16- (2- trifluoromethyl-pmdin-4- il) - 1 H-indol-2-ill-methanone
502502
12.69 (bs, 1H), 11.98 (s, 1H), 8.83 (d, 1H, J = 4 Hz), 8.31 (m, 1H), 8.16 (m, 1H), 8.05 (d, 1H, J = 4 Hz), 7.94 (s, 1H), 7.86 (d, 1H, J = 8 Hz), 7.62 (m, 3H), 7.54 (m, 1H), 7.31 (d, 1H, J =8 Hz), 7.07(bs, 2H), 2.55 (s,3H)12.69 (bs, 1H), 11.98 (s, 1H), 8.83 (d, 1H, J = 4 Hz), 8.31 (m, 1H), 8.16 (m, 1H), 8.05 (d, 1H, J = 4 Hz ), 7.94 (s, 1H), 7.86 (d, 1H, J = 8 Hz), 7.62 (m, 3H), 7.54 (m, 1H), 7.31 (d, 1H, J = 8 Hz), 7.07 (bs , 2H), 2.55 (s, 3H)
[5-am¡no-1-(2-met¡l-1 H- bencimidazol-5-il)-1 H- pirazol-4-il]-[5-(3,3-difluoro- pirrolidina-1- carbon¡l)-1H- indol-1-ill-metanona[5-amine-1- (2-methyl-1 H- benzimidazol-5-yl) -1 H- pyrazol-4-yl] - [5- (3,3-difluoro-pyrrolidine-1- carbon¡l) -1H- indole-1-ill-methanone
490490
8.33 (bs, 1H), 8.03 (bs, 1H), 7.81 (m, 2H), 7.56 (m, 2H), 7.50 (m, 2H), 4.24 (t, 4 H, J = 12 Hz), 2.66 (s, 3H), 1.49 (m, 1H), 1.39 (m, 3H), 1.28 (m, 4H)8.33 (bs, 1H), 8.03 (bs, 1H), 7.81 (m, 2H), 7.56 (m, 2H), 7.50 (m, 2H), 4.24 (t, 4 H, J = 12 Hz), 2.66 ( s, 3H), 1.49 (m, 1H), 1.39 (m, 3H), 1.28 (m, 4H)
[5-am¡no-1-(2-metil-1 H- benc¡m¡dazol-5-il)-1H- p¡razol-4-N]-[5-(2,6-d¡met¡l- morfolina-4- carbonil)-1H- ¡ndol-2-ill-metanona[5-am-1-1 (2-methyl-1 H- benzyldazol-5-yl) -1 H- prazol-4-N] - [5- (2,6-d-met] L- morpholine-4- carbonyl) -1H- ndol-2-ill-methanone
498498
12.46 (d, 1H, J = 4 Hz), 11.91 (s, 1H), 8.32 (m, 1H), 7.77 (m, 1H), 7.65 (m, 1H), 7.56 (m, 1 H), 7.51 (m, 1H), 7.27 (m, 2H), 7.05 (s, 1H), 7.0 (s, 1H), 3.55 (bs, 2H), 2.62 (s, 3H), 1.23 (m, 5H), 1.07(bs,3H12.46 (d, 1H, J = 4 Hz), 11.91 (s, 1H), 8.32 (m, 1H), 7.77 (m, 1H), 7.65 (m, 1H), 7.56 (m, 1 H), 7.51 ( m, 1H), 7.27 (m, 2H), 7.05 (s, 1H), 7.0 (s, 1H), 3.55 (bs, 2H), 2.62 (s, 3H), 1.23 (m, 5H), 1.07 (bs , 3H
[5-amino-1-(2-met¡l-1 H- bencimidazol-5-¡l)-1 H- pirazol-4-il]-[5-([1,4’] bipiperidinil-1’- carbonil)- 1 H-indol-2-il]-metanona[5-amino-1- (2-methyl-1 H- benzimidazol-5-l) -1 H- pyrazol-4-yl] - [5 - ([1,4 '] bipiperidinyl-1'- carbonyl) - 1 H-indol-2-yl] -methanone
551551
8.28 (s, 1H), 7.83 (s, 1H), 7.63 (m, 2H), 7.55 (m, 1H), 7.45 (s, 1H), 7.32 (d, 2H, 7.05 (s, 1H, J = 8 Hz), 2.60 (m, 8H), 1.88 (m, 2H), 1.62 (m, 4H)8.28 (s, 1H), 7.83 (s, 1H), 7.63 (m, 2H), 7.55 (m, 1H), 7.45 (s, 1H), 7.32 (d, 2H, 7.05 (s, 1H, J = 8 Hz), 2.60 (m, 8H), 1.88 (m, 2H), 1.62 (m, 4H)
[5-amino-1-(2-met¡l-1 H- bencimidazol-5-¡l)-1 H- pirazol-4-il]-{5-[4-(2,2,2- tr¡fluoroetil)-p¡peraz¡na-1- carbon¡l]-1 H-indol- 2-il}- metanona[5-amino-1- (2-methyl-1 H- benzimidazol-5-l) -1 H- pyrazol-4-yl] - {5- [4- (2,2,2- tr¡ fluoroethyl) -p¡peraz¡na-1- carbon¡l] -1 H-indole-2-yl} - methanone
551551
8.28 (s, 1H), 7.84 (s, 1H), 7.64 (d, 2H, J = 8 Hz), 7.55 (d, 1H, J = 8.68 Hz), 7.45 (s, 1H), 7.35 (t, 1H, J = 8 Hz), 3.67 (bs, 4H), 3.17 (t, 2H, J = 8 Hz), 2.74 (m, 4H), 2.36 (s, 3H),8.28 (s, 1H), 7.84 (s, 1H), 7.64 (d, 2H, J = 8 Hz), 7.55 (d, 1H, J = 8.68 Hz), 7.45 (s, 1H), 7.35 (t, 1H , J = 8 Hz), 3.67 (bs, 4H), 3.17 (t, 2H, J = 8 Hz), 2.74 (m, 4H), 2.36 (s, 3H),
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 236 236
- r. O sftrOTi- ■v. ¡r ■'' ■? [5-amino-1-(2-metil-1H- bencimidazol-5-il)-1 H-pirazol-4-il]- {5-[4-(2-hi droxi eti I)- pi perazi na-1 - carbonil]-1 H-indol- 2-il}-metanona 513 8.28 (s, 1H), 7.84 (s, 1H), 7.65 (m, 2H), 7.55 (d, 1H, J= 8 Hz), 7.46 (s, 1H), 7.35 (m, 2H), 3.69 (m, 6H), 6.82 (m, 3H), 3.33 (s, 1H), 2.64 (s, 3H), 2.56 (m, 6 H) r. Or sftrOTi- ■ v. ¡R ■ '' ■? [5-amino-1- (2-methyl-1H- benzimidazol-5-yl) -1 H -pyrazol-4-yl] - {5- [4- (2-hi droxi eti I) - pi perazi na- 1-carbonyl] -1 H-indole-2-yl} -methanone 513 8.28 (s, 1H), 7.84 (s, 1H), 7.65 (m, 2H), 7.55 (d, 1H, J = 8 Hz), 7.46 (s, 1H), 7.35 (m, 2H), 3.69 (m, 6H), 6.82 (m, 3H), 3.33 (s, 1H), 2.64 (s, 3H), 2.56 (m, 6 H)
- 237 237
- c ■ H -V X [5-amino-1-(2-metil-1H- bencimidazol-5-il)-1 H-pirazol-4-il]- [5-(3,3,4,4-tetrafluoropi rrolidina-1- carbonil)-1H-indol-2-il]-metanona 526 8.289 (s, 1H), 7.99 (m, 1H), 7.65 (m, 2H), 7.55 (m, 1H), 7.47 (m, 2H), 7.39 (d, 1H, J = 8 Hz), 3.95 (t, 2H, J = 12 Hz), 3.87 (t, 2H, J = 8 Hz), 2.61 (s,3H), 2.45(bs, 2H) c ■ H -VX [5-amino-1- (2-methyl-1H- benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [5- (3,3,4,4-tetrafluoropi rrolidine -1- carbonyl) -1H-indole-2-yl] -methanone 526 8,289 (s, 1H), 7.99 (m, 1H), 7.65 (m, 2H), 7.55 (m, 1H), 7.47 (m, 2H ), 7.39 (d, 1H, J = 8 Hz), 3.95 (t, 2H, J = 12 Hz), 3.87 (t, 2H, J = 8 Hz), 2.61 (s, 3H), 2.45 (bs, 2H )
- 238 238
- r r^cr HTd \L C [5-amino-1-(2-metil-1H- bencimidazol-5-il)-1 H-pirazol-4-il]- [5-((R)-3-fluoro-pirrolidina-1- carbonil)-1H-indol-2-il]-metanona 472 8.29 (s, 1H), 7.97 (d, 1H, J=12 Hz), 7.67 (m, 2H), 7.55 (m, 1H), 7.47 (m, 2H), 7.37 (d, 2H, J=8 Hz), 5.3 (m, 1H), 3.84 (m, 6H), 2.61 (s, 3H) rr ^ cr HTd \ LC [5-amino-1- (2-methyl-1H- benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [5 - ((R) -3-fluoro-pyrrolidine -1- carbonyl) -1H-indole-2-yl] -methanone 472 8.29 (s, 1H), 7.97 (d, 1H, J = 12 Hz), 7.67 (m, 2H), 7.55 (m, 1H), 7.47 (m, 2H), 7.37 (d, 2H, J = 8 Hz), 5.3 (m, 1H), 3.84 (m, 6H), 2.61 (s, 3H)
- 239 239
- <r [5-amino-1-(2-metil-1H- bencimidazol-5-il)-1H-pirazol-4-il]- [5-((S)-3-fluroro-pirrolidina-1- carbonil)-1H-indol-2-il]-metanona 472 8.29 (s, 1H), 7.97 (d, 1H), 7.65 (m, 2H), 7.55 (m, 1H,), 7.47 (m, 2H), 7.35 (d, 1H, J = 8 Hz), 5.3 (m, 1 H), 3.77 (m, 4H), 2.61 (s, 3H), 2.2 (bs, 2H) <r [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [5 - ((S) -3-fluroro-pyrrolidine-1-carbonyl) -1H-indole-2-yl] -methanone 472 8.29 (s, 1H), 7.97 (d, 1H), 7.65 (m, 2H), 7.55 (m, 1H,), 7.47 (m, 2H), 7.35 ( d, 1H, J = 8 Hz), 5.3 (m, 1 H), 3.77 (m, 4H), 2.61 (s, 3H), 2.2 (bs, 2H)
[Ejemplo 90: Síntesis de la [5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-¡l]-(3-fluoro-1H-indol-2-¡l)- metanona][Example 90: Synthesis of [5-amino-1- (2-methyl-1H-benzyldazol-5-yl) -1H-pyrazol-4-l] - (3-fluoro-1H -indole-2-¡l) - methanone]
55
[5-Amino-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-[3-fluoro-1-(tolueno-4-sulfon¡l)-1H-¡ndol-2-¡l]-metanona (25.0 mg, 0.041 mmol) se disolvió en ácido metanosulfónico (0.25 mi), y se agitó a temperatura ambiente, durante una hora. El pH de la mezcla de reacción se ajustó a 6 utilizando una solución acuosa de hidróxido de sodio 1 M. Después de la extracción con acetato de etilo, el extracto se secó sobre sulfato de sodio anhidro. El desecante se 10 eliminó por filtración. El filtrado se concentró bajo presión reducida, y el residuo resultante se purificó por cromatografía de columna de sílica gel (diclorometano /metanol = 60/1 a 40/1) para dar[5-Amino-1- (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-l] - [3-fluoro-1- (toluene- 4-sulfon¡l) -1H-¡ndol-2-¡l] -methanone (25.0 mg, 0.041 mmol) was dissolved in methanesulfonic acid (0.25 ml), and stirred at room temperature, for one hour. The pH of the reaction mixture was adjusted to 6 using a 1 M aqueous solution of sodium hydroxide. After extraction with ethyl acetate, the extract was dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane / methanol = 60/1 to 40/1) to give
la [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(3-fluoro-1H-indol-2-il)-metanona, obtenida como un sólido de color amarillo pálido (8.7 g, con un rendimiento del 55%).the [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (3-fluoro-1H-indole-2-yl) -methanone, obtained as a pale yellow solid (8.7 g, with a yield of 55%).
1H-RMN (DMSO-De) 8 12.48 (1H, s), 11.50 (1H, s), 8.03 (1H, d, J = 3.1 Hz), 7.69 (1H, d, J = 8.5 Hz), 7.62 (2H, s), 15 7.45 (1H, d, J = 8.5 Hz), 7.25-7.35 (2H, m), 7.15 (1H, t, J = 7.3 Hz), 7.05 (2H, s), 2.53 (3H, s)1H-NMR (DMSO-De) 8 12.48 (1H, s), 11.50 (1H, s), 8.03 (1H, d, J = 3.1 Hz), 7.69 (1H, d, J = 8.5 Hz), 7.62 (2H , s), 15 7.45 (1H, d, J = 8.5 Hz), 7.25-7.35 (2H, m), 7.15 (1H, t, J = 7.3 Hz), 7.05 (2H, s), 2.53 (3H, s )
ESI (LC-MS modo positivo) m/z 375 [(M+H)+jESI (LC-MS positive mode) m / z 375 [(M + H) + j
Los compuestos de los Ejemplos 91 a 131 enumerados en la Tabla 4, se sintetizaron mediante el mismo método como en el Ejemplo 90.The compounds of Examples 91 to 131 listed in Table 4, were synthesized by the same method as in Example 90.
Tabla 4Table 4
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 91 91
- [5-amlno-1-(2-metll-1H- bencimidazol-5-il)- 1 Hpirazol- 4-il] -[5-(1- ¡sopropll-plperldln-4-il)- 6-trlfluorometll-1H- ¡ndol-2-¡l]-metanona 550 1H-RMN (DMSO-D6) 8: 12.48 (1H, s), 11.99 (1H, s), 8.30 (1H, s), 7.87 (1H, s), 7.79 (1H, s), 7.66-7.55 (2H, br m), 7.45 (1H, s), 7.29 (1H, d, J = 8.5 Hz), 7.06 (2H, br s), 2.96-2.89 (2H, m), 2.84-2.70 (2H, m), 2.53 (3H, s), 2.25-2.18 (2H, m), 1.81- 1.71 (4H, m), 1.01 (6H, d, J = 6.7 Hz). [5-amlno-1- (2-metll-1H- benzimidazol-5-yl) - 1 Hpirazol-4-yl] - [5- (1- sopropll-plperldln-4-yl) - 6-trlfluorometll-1H - ¡ndol-2-¡l] -methanone 550 1H-NMR (DMSO-D6) 8: 12.48 (1H, s), 11.99 (1H, s), 8.30 (1H, s), 7.87 (1H, s), 7.79 (1H, s), 7.66-7.55 (2H, br m), 7.45 (1H, s), 7.29 (1H, d, J = 8.5 Hz), 7.06 (2H, br s), 2.96-2.89 (2H, m), 2.84-2.70 (2H, m), 2.53 (3H, s), 2.25-2.18 (2H, m), 1.81-1.71 (4H, m), 1.01 (6H, d, J = 6.7 Hz).
- 92 92
- H 2-[5-amino-1-(2-met¡l- 1 H-bencimidazol-5-il)- 1 Hpirazol-4-carbonilj- 1 H-indol-6-carbonitrilo 382 1H-RMN (DMSO-D6) 8: 12.47 (1H, s), 12.24 (1H, s), 8.33 (1H, s), 7.93-7.86 (2H,m), 7.67-7.55 (3H, m), 7.42 (1H, dd, J =8.5, 1.2 Hz), 7.29 (1H, dd, J = 8.5, 1.8 Hz), 7.10 (2H, s), 2.54 (3H,s). H 2- [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4-carbonylj-1 H-indole-6-carbonitrile 382 1 H-NMR (DMSO-D6 ) 8: 12.47 (1H, s), 12.24 (1H, s), 8.33 (1H, s), 7.93-7.86 (2H, m), 7.67-7.55 (3H, m), 7.42 (1H, dd, J = 8.5, 1.2 Hz), 7.29 (1H, dd, J = 8.5, 1.8 Hz), 7.10 (2H, s), 2.54 (3H, s).
- 93 93
- H [5-am¡ no-1 -(2-met¡l-1 H- benclmidazol-5-il)- 1 Hpirazol-4-M] -[5- (1,2,3,6-tetrahidro- plrldln-4-ll) -1 H-indol-2- ¡l]-metanona 438 1H-MMR (DMSO-D6) 8: 12.45 (1H, s), 11.65 (1H, s), 8.28 (1H, s), 7.67-7.54 (3H, mi, 7.44-7.39 (3H, m), 7.29 (1H, d, J = 8.5 Hz), 6.99 (2H, br s), 6.16 (1H, s), 3.41- 3.38 (2H, m), 2.95 (2H, t, J = 5.5 Hz), 2.53 (3H, s), 2.43-2.41 (2H, m). H [5-am¡ no-1 - (2-methyl-1 H- benclmidazol-5-yl) - 1 Hpyrazol-4-M] - [5- (1,2,3,6-tetrahydro-plrldln -4-ll) -1 H-indole-2- 1] -methanone 438 1H-MMR (DMSO-D6) 8: 12.45 (1H, s), 11.65 (1H, s), 8.28 (1H, s), 7.67-7.54 (3H, mi, 7.44-7.39 (3H, m), 7.29 (1H, d, J = 8.5 Hz), 6.99 (2H, br s), 6.16 (1H, s), 3.41- 3.38 (2H, m), 2.95 (2H, t, J = 5.5 Hz), 2.53 (3H, s), 2.43-2.41 (2H, m).
- 94 94
- •»a%r [5-amlno-1-2-met¡l-1H- benclmidazol-5-ll- 1 Hpirazol-4-il] -(5- piper¡din-4-¡l-1 H-indol- 2-¡l)-metanona 440 1H-RMN (DMSO-D6) 8: 12.44 (1H, s), 11.55 (1H, s), 8.28 (1H, s), 7.66-7.55 (2H, br m), 7.48 (1H, s), 7.40 (1H, d, J = 8.5 Hz), 7.37 (1H, d, J = 1.2 Hz), 7.29 (1H, d, J = 8.5 Hz), 7.15 (1H, dd, J = 8.5, 1.2 Hz), 6.97 (2H, br s), 3.05-3.02 (2H, m), 2.67- 2.58 (3H, m), 2.53 (3H, s), 1.75-1.72 (2H, m), 1.61-1.50 (2H, m). • »a% r [5-amlno-1-2-metl-1H- benclmidazol-5-ll- 1 Hpirazol-4-yl] - (5- piperine-4-l-1 H-indole - 2-¡l) -methanone 440 1H-NMR (DMSO-D6) 8: 12.44 (1H, s), 11.55 (1H, s), 8.28 (1H, s), 7.66-7.55 (2H, br m), 7.48 (1H, s), 7.40 (1H, d, J = 8.5 Hz), 7.37 (1H, d, J = 1.2 Hz), 7.29 (1H, d, J = 8.5 Hz), 7.15 (1H, dd, J = 8.5, 1.2 Hz), 6.97 (2H, br s), 3.05-3.02 (2H, m), 2.67-2.58 (3H, m), 2.53 (3H, s), 1.75-1.72 (2H, m), 1.61 -1.50 (2H, m).
- 95 95
- u C ¡fH- ,0^ [5-amino-1-(2-metil-1H- bencimidazol-5-il)- 1 Hpirazol-4-il] -[5-((Rj- 3- fluoro-pirrolidi n-1 - ilmetil)-1 H-indol-2-ilj- metanona 458 1H-RMN (DMSO-D6) 8: 12.46 (1H, d, J = 4.9 Hz), 11.65 (1H, d, J = 1.2 Hz), 8.30 (1H, d, J = 4.9 Hz), 7.65 (1H, dd, J = 5.2, 3.4 Hz), 7.59-7.57 (2H, m), 7.44-7.42 (2H, m), 7.32-7.27 (1H, m), 7.23 (1H, dd, J = 8.2, 1.5 Hz), 6.99 (2H, d, J = 22.0 Hz), 5.20 (1H, dt, J = 55.9, 5.6 Hz), 3.67 (2H, s), 2.81-2.75 (2H, m), 2.65-2.68 (1H, m), 2.54 (3H, s), 2.34-2.32 (1H, m), 2.18-2.13 (1H, m), 1.90-1.84 (1H, mi). u C ¡fH-, 0 ^ [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1 Hpirazol-4-yl] - [5 - ((Rj- 3- fluoro-pyrrolidi n -1 - ilmethyl) -1 H-indole-2-yl-methanone 458 1H-NMR (DMSO-D6) 8: 12.46 (1H, d, J = 4.9 Hz), 11.65 (1H, d, J = 1.2 Hz) , 8.30 (1H, d, J = 4.9 Hz), 7.65 (1H, dd, J = 5.2, 3.4 Hz), 7.59-7.57 (2H, m), 7.44-7.42 (2H, m), 7.32-7.27 (1H , m), 7.23 (1H, dd, J = 8.2, 1.5 Hz), 6.99 (2H, d, J = 22.0 Hz), 5.20 (1H, dt, J = 55.9, 5.6 Hz), 3.67 (2H, s) , 2.81-2.75 (2H, m), 2.65-2.68 (1H, m), 2.54 (3H, s), 2.34-2.32 (1H, m), 2.18-2.13 (1H, m), 1.90-1.84 (1H, me).
- 96 96
- d ít [5-am¡ no-1 -(2-metil-1H- bendmidazol-5-il)- 1Hp¡razol-4-¡l] -(6- fluoro-5- piperidin-4-il- 1H-¡ndol -2-¡l)- metanona 458 1H-RMN (DLSO-D6) 8: 12.45 (1H, s), 11.63 (1H, s), 8.27 (1H, s), 7.62-7.59 (2H, br m), 7.55 (1H, d, J = 7.3 Hz), 7.43 (1H. s), 7.28 (1H, dd, J = 8.5, 2.4 Hz), 7.14 (1H, d, J = 11.0 Hz), 6.97 (2H, br s), 3.06-3.03 (2H, m), 2.91-2.85 (1H, m), 2.66-2.59 (2H, m). 2.53 (3H, s), 1.75-1.72 (2H, m), 1.63- 1.53 (2H, m). d ít [5-am¡ no-1 - (2-methyl-1H- bendmidazol-5-yl) - 1Hp¡razol-4-¡l] - (6- fluoro-5- piperidin-4-il- 1H- Ndol -2-¡l) - methanone 458 1H-NMR (DLSO-D6) 8: 12.45 (1H, s), 11.63 (1H, s), 8.27 (1H, s), 7.62-7.59 (2H, br m ), 7.55 (1H, d, J = 7.3 Hz), 7.43 (1H. S), 7.28 (1H, dd, J = 8.5, 2.4 Hz), 7.14 (1H, d, J = 11.0 Hz), 6.97 (2H , br s), 3.06-3.03 (2H, m), 2.91-2.85 (1H, m), 2.66-2.59 (2H, m). 2.53 (3H, s), 1.75-1.72 (2H, m), 1.63-1.53 (2H, m).
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 97 97
- [5-amino-1-(2-metil- 1 H-bencimidazol-5-il)- 1 Hpirazol- 4-¡l] -[6- fluoro-5-(1- metil- piperidin-4-il)-1 H-¡ndol- 2-¡l]-metanona 472 1H-RMN (DMSO-D6) 6: 12.45 (1H, s), 11.64 (1H, d, J = 1.5 Hz), 8.27 (1H, s), 7.66-7.62 (1H), br m), 7.59-7.53 (1H, br m), 7.67 (1H, d, J = 7.3 Hz), 7.42 (1H, d, J = 1.5 Hz), 7.28 (1H, d, J = 9.8 Hz), 7.14 (1H, d, J = 11.6 Hz), 6.97 (2H, br s), 2.92- 2.87 (2H, m), 2.79-2.72 (1H, m), 2.53 (3H, s), 2.21 (3H, s), 2.04-1.97 (2H, m), 1.78- 1.69 (4H, m). [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4-yl] - [6- fluoro-5- (1- methyl-piperidin-4-yl) - 1 H-¡ndol- 2-¡l] -methanone 472 1H-NMR (DMSO-D6) 6: 12.45 (1H, s), 11.64 (1H, d, J = 1.5 Hz), 8.27 (1H, s), 7.66-7.62 (1H), br m), 7.59-7.53 (1H, br m), 7.67 (1H, d, J = 7.3 Hz), 7.42 (1H, d, J = 1.5 Hz), 7.28 (1H, d , J = 9.8 Hz), 7.14 (1H, d, J = 11.6 Hz), 6.97 (2H, br s), 2.92-287 (2H, m), 2.79-2.72 (1H, m), 2.53 (3H, s ), 2.21 (3H, s), 2.04-1.97 (2H, m), 1.78-1.69 (4H, m).
- 98 98
- [5-amino-1-(2-metil- 1 H-bencimidazol-5-il)- 1 H-il]-[5-(1 -isopropll- piperidin-4-il)-1 H-indol- 2-¡l]-metanona 482 1H-RMN (DMSO-D6) 6: 12.45 (1H, s), 11.55 (1H, d, J = 1.8 Hz), 8.28 (1H, s), 7.65-7.63 (1H, br m), 7.59-7.56 (1H, br m), 7.49 (1H. s), 7.39 (1H, d. J = 8.5 Hz), 7.36 (1H, d, J = 1.5 Hz), 7.29 (1H, d, J = 9.1 Hz), 7.18 (1H, dd, J = 8.5, 1.5 Hz), 7.00 (1H, br s), 6.85 (1H, br s), 2.92-2.87 (2H, m), 2.76-2.68 (1H, m), 2.55-2.52 (1H, m), 2.53 (3H, s), 227-2.20 (2H, m), 1.83- 1.77 (2H, m), 1.71-1.60 (2H, m), 1.00 (6H, d, J = 6.7 Hz). [5-amino-1- (2-methyl- 1 H-benzimidazol-5-yl) -1 H-yl] - [5- (1-isopropll-piperidin-4-yl) -1 H-indole-2- L] -methanone 482 1H-NMR (DMSO-D6) 6: 12.45 (1H, s), 11.55 (1H, d, J = 1.8 Hz), 8.28 (1H, s), 7.65-7.63 (1H, br m ), 7.59-7.56 (1H, br m), 7.49 (1H. S), 7.39 (1H, d. J = 8.5 Hz), 7.36 (1H, d, J = 1.5 Hz), 7.29 (1H, d, J = 9.1 Hz), 7.18 (1H, dd, J = 8.5, 1.5 Hz), 7.00 (1H, br s), 6.85 (1H, br s), 2.92-2.87 (2H, m), 2.76-2.68 (1H, m), 2.55-2.52 (1H, m), 2.53 (3H, s), 227-2.20 (2H, m), 1.83-1.77 (2H, m), 1.71-1.60 (2H, m), 1.00 (6H, d, J = 6.7 Hz).
- 99 99
- H-/ [5-amlno-1-(2-met¡l- 1 H-benclmldazol-5-il)- 1 Hpirazol-1 -il] -[6- fluoro-5-(1- ¡sopropil- piperidin-4-¡l)-1 H-indol- 2-¡l]-metanona 500 1H-RMN (DMSO-D6) 8: 12.45 (1H, s), 11.64 (1H, d, J = 1.5 Hz), 8.27 (1H, s), 7.66-7.61 (1H, br m), 7.59-7.55 (1H, br m), 7.57 (1H, d, J = 7.3 Hz), 7.41 (1H, d, J = 1.5 Hz), 7.28 (1H, d, J = 7.9 Hz), 7.14 (1H, d, J = 11.6 Hz), 7.00 (1H, br s), 6.95 (1H, br s), 2.93-2.88 (2H, m), 2.77-2.69 (2H, m), 2.53 (3H, s), 2.30-2.22 (2H, m), 1.84-1.78 (2H, m), 1.75-1.65 (2H, m), 1.01 (6H, d, J =6.7 Hz). H- / [5-amlno-1- (2-methyl-1 H-benclmldazol-5-yl) - 1 Hpyrazol-1-yl] - [6- fluoro-5- (1- sopropyl-piperidin- 4-¡1) -1 H-indole-2-¡1 -methanone 500 1H-NMR (DMSO-D6) 8: 12.45 (1H, s), 11.64 (1H, d, J = 1.5 Hz), 8.27 ( 1H, s), 7.66-7.61 (1H, br m), 7.59-7.55 (1H, br m), 7.57 (1H, d, J = 7.3 Hz), 7.41 (1H, d, J = 1.5 Hz), 7.28 (1H, d, J = 7.9 Hz), 7.14 (1H, d, J = 11.6 Hz), 7.00 (1H, br s), 6.95 (1H, br s), 2.93-2.88 (2H, m), 2.77- 2.69 (2H, m), 2.53 (3H, s), 2.30-2.22 (2H, m), 1.84-1.78 (2H, m), 1.75-1.65 (2H, m), 1.01 (6H, d, J = 6.7 Hz)
- 100 100
- ^ 0 » ¡W' fwAV^'-O"- N=/ ’,,=íi1 [5-amlno-1-(2-metil- 1 H-benclmldazol-5-il)- 1 Hpirazol-4-il]-(6- piridin-3-il-1 H-indol-2- ¡l)-metanona 434 1H-RMN (DMSO-D6) 8: 12.47 (1H, s), 11.86 (1H, s), 8.90 (1H. d, J = 2.4 Hz), 8.56 (1H, d, J = 4.9 Hz), 8.34 (1H, s), 8.08 (1H, d, J = 7.9 Hz), 7.83 (1H, d, J = 7.9 Hz, 7.73 (1H, s), 7.62 (2H, s), 7.53-7.43 (3H, m), 7.30 (2H, dd, J = 8.2, 1.5 Hz), 7.03 (3H, s), 2.54 (3H, s). ^ 0 »W 'fwAV ^' - O" - N = / ',, = íi1 [5-amlno-1- (2-methyl- 1 H-benclmldazol-5-yl) - 1 Hpirazol-4-il] - (6- pyridin-3-yl-1 H-indole-2- 1) -methanone 434 1 H-NMR (DMSO-D6) 8: 12.47 (1H, s), 11.86 (1H, s), 8.90 (1H .d, J = 2.4 Hz), 8.56 (1H, d, J = 4.9 Hz), 8.34 (1H, s), 8.08 (1H, d, J = 7.9 Hz), 7.83 (1H, d, J = 7.9 Hz , 7.73 (1H, s), 7.62 (2H, s), 7.53-7.43 (3H, m), 7.30 (2H, dd, J = 8.2, 1.5 Hz), 7.03 (3H, s), 2.54 (3H, s ).
- 101 101
- o'"’ [5-amlno-1-(2-metil- 1 H-benclmldazol-5-il)- 1 Hpirazol-4-il] -[5-(6- morfol¡n-4-il-piridin-3-M) -1 H-indol-2-il]- metanona 519 1H-RMN (DMSO-D6) 8: 12.47 (1H, s), 11.74 (1H, d, J = 1.2 Hz), 8.49 (1H, d, J = 2.4 Hz), 8.32 1H, s), 7.91-7.90 (2H, m), 7.66-7.47 (5H, m), 7.30 (1H, d, J = 8.5 Hz), 7.02 (2H, d, J = 19.5 6.94 (1H, d, J = 9.2 Hz), 3.73 (4H, dd, J = 4.6, 2.3 Hz), 3.49 (4H, dd, J = 4.9, 2.4 Hz), 2.54 (3H, s)- or '"' [5-amlno-1- (2-methyl- 1 H-benclmldazol-5-yl) -1 Hpirazol-4-yl] - [5- (6- morphol-4-yl-pyridin- 3-M) -1 H-indole-2-yl] - methanone 519 1H-NMR (DMSO-D6) 8: 12.47 (1H, s), 11.74 (1H, d, J = 1.2 Hz), 8.49 (1H, d, J = 2.4 Hz), 8.32 1H, s), 7.91-7.90 (2H, m), 7.66-7.47 (5H, m), 7.30 (1H, d, J = 8.5 Hz), 7.02 (2H, d, J = 19.5 6.94 (1H, d, J = 9.2 Hz), 3.73 (4H, dd, J = 4.6, 2.3 Hz), 3.49 (4H, dd, J = 4.9, 2.4 Hz), 2.54 (3H, s) -
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 102 102
- n K [5-amino-1-(2-metil-1H- bencimidazol-5-il)- 1Hpirazol- 4-il] -(5- piridin-3-il-1 H-indol-2-il)- metanona 434 1H-RMN (DMSO-D6) 8: 12.47 (1H, s), 11.85 (1H, d, J = 1.8 Hz), 8.93 (1H, d. J = 2.4 Hz), 8.54 (1H, dd, J = 4.9, 1.2 Hz), 8.33 (1H, s), 8.10 (1H, dt, J = 8.1, 1.8 Hz), 8.03 (1H, s), 7.64-7.59 (4H, m), 7.52 (1H, d, J = 1.8 Hz), 7.49 (1H, dd, J = 7.6, 4.6 Hz), 7.31 (1H, d, J = 8.5 Hz), 7.03 (2H, d, J = 20.1 Hz), 2.54 (3H, s). n K [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1Hpirazol-4-yl] - (5- pyridin-3-yl-1 H-indole-2-yl) -methanone 434 1H-NMR (DMSO-D6) 8: 12.47 (1H, s), 11.85 (1H, d, J = 1.8 Hz), 8.93 (1H, d. J = 2.4 Hz), 8.54 (1H, dd, J = 4.9, 1.2 Hz), 8.33 (1H, s), 8.10 (1H, dt, J = 8.1, 1.8 Hz), 8.03 (1H, s), 7.64-7.59 (4H, m), 7.52 (1H, d, J = 1.8 Hz), 7.49 (1H, dd, J = 7.6, 4.6 Hz), 7.31 (1H, d, J = 8.5 Hz), 7.03 (2H, d, J = 20.1 Hz), 2.54 (3H, s).
- 103 103
- - f1 f [5-amino-1-(2-metil-1H- bencimidazol-5-il)- 1Hpirazol- 4-il] -[5-(6- piperazin-1 -il-piridin-3- il)- 1 H-indol-2-il]- metanona 518 1H-RMN (DMSO-D6] 8: 12.48 (1H, s), 11.74 (1H, s), 8.45 (1H, d, J = 3.1 Hz), 8.32 (1H, s), 7.87-7.85 (2H, m), 7.697.49 (5H, m), 7.47 (1H, s), 7.30 (1H, dd, J = 8.5, 1.8 Hz), 7.02 (2H, s), 6.89 (1H, d, J = 9.2 Hz), 3.44 (4H, t, J = 5.1 Hz), 2.80 (4H, t, J = 5.1 Hz), 2.54 (3H, s). - f1 f [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) - 1-pyrazol-4-yl] - [5- (6- piperazin-1-yl-pyridin-3- yl) - 1 H-indole-2-yl] - methanone 518 1H-NMR (DMSO-D6] 8: 12.48 (1H, s), 11.74 (1H, s), 8.45 (1H, d, J = 3.1 Hz), 8.32 ( 1H, s), 7.87-7.85 (2H, m), 7.697.49 (5H, m), 7.47 (1H, s), 7.30 (1H, dd, J = 8.5, 1.8 Hz), 7.02 (2H, s) , 6.89 (1H, d, J = 9.2 Hz), 3.44 (4H, t, J = 5.1 Hz), 2.80 (4H, t, J = 5.1 Hz), 2.54 (3H, s).
- 104 104
- JJ <-X3Q- [5-amino-1-(2-metil-1H- bencimidazol-5-il)- 1Hpirazol- 4-il] -[5-(6- hidroxipiridin- 3-il)-1H- indol-2-il]-metanona 450 1H-RMN (DMSO-D6) 8: 12.89 (1H, s), 11.76 (1H, s), 8.38 (1H, s), 8.00 (1H, d, J = 1.8 Hz), 7.95 (1H, d, J = 9.2 Hz). 7.88 (1H, dd, J = 9.7. 2.5 Hz, 7.82 (1H, s), 7.73 (1H, dd, J = 8.5, 1.8 Hz). 7.67 (1H, d, J = 2.5 Hz), 7.52-7.48 (4H, m). 7.25 (2H, s), 6.47 (1H, d, J = 9.7 Hz), 2.84 (3H, s). JJ <-X3Q- [5-amino-1- (2-methyl-1H- benzimidazol-5-yl) - 1 Hpirazol-4-yl] - [5- (6- hydroxypyridin-3-yl) -1H- indole- 2-yl] -methanone 450 1H-NMR (DMSO-D6) 8: 12.89 (1H, s), 11.76 (1H, s), 8.38 (1H, s), 8.00 (1H, d, J = 1.8 Hz), 7.95 (1H, d, J = 9.2 Hz). 7.88 (1H, dd, J = 9.7. 2.5 Hz, 7.82 (1H, s), 7.73 (1H, dd, J = 8.5, 1.8 Hz) 7.67 (1H, d, J = 2.5 Hz), 7.52-7.48 ( 4H, m) 7.25 (2H, s), 6.47 (1H, d, J = 9.7 Hz), 2.84 (3H, s).
- 105 105
- [5-amino-1-(2-metil-1H- bencimidazol-5-il)- 1 Hpirazol-4-il] -[6-fluoro- 5-(4- metil-piperazin-1- ilmetil)-1 H-indol-2-il]- metanona 487 1H-RMN (DMSO-D6) 8: 12.47 (1H, s), 11.71 (1H, s), 8.29 (1H, s), 7.65 (1H, d. J = 7.3 Hz), 7.62-7.57 (2H, br m). 7.46 (1H, s), 7.28 (1H, dd, J = 8.5, 1.8 Hz), 7.15 (1H, d, J = 11.0 Hz), 6.99 (2H, br s), 3.56 (2H, s), 2.53 (3H, s), 2.47-2.38 (4H, br m). 2.35-2.28 (4H, brm), 2.14 (3H, s). [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 Hpirazol-4-yl] - [6-fluoro-5- (4- methyl-piperazin-1- ylmethyl) -1 H -indole-2-yl] - methanone 487 1H-NMR (DMSO-D6) 8: 12.47 (1H, s), 11.71 (1H, s), 8.29 (1H, s), 7.65 (1H, d. J = 7.3 Hz), 7.62-7.57 (2H, br m). 7.46 (1H, s), 7.28 (1H, dd, J = 8.5, 1.8 Hz), 7.15 (1H, d, J = 11.0 Hz), 6.99 (2H, br s), 3.56 (2H, s), 2.53 ( 3H, s), 2.47-2.38 (4H, br m). 2.35-2.28 (4H, brm), 2.14 (3H, s).
- 106 106
- [5-amino-1-(2-metil-1H- bencimidazol-5-il)- 1 Hpirazol-4-il] -(6-fluoro- 5- pirrolidi n-1-ilmetil-1 H- indol- 2-il)-metanona 458 1H-RMN (DMSO-D6) 8: 12.48 (1H, s), 11.69 (1H, s), 8.29 (1H, s), 7.67 (1H, d, J = 7.3 Hz), 7.62-7.58 (2H, br m), 7.45 (1H, s), 7.28 (1H, dd, J = 8.5, 1.8 Hz), 7.14 (1H, d, J = 11.0 Hz), 6.99 (2H, br s), 3.68 (2H, s), 2.53 (3H, s), 2.52-2.45 (4H, m), 1.72-1.67 (4H, m). [5-amino-1- (2-methyl-1H- benzimidazol-5-yl) -1 Hpirazol-4-yl] - (6-fluoro-5- pyrrolidi n-1-ylmethyl-1 H- indole-2- il) -methanone 458 1H-NMR (DMSO-D6) 8: 12.48 (1H, s), 11.69 (1H, s), 8.29 (1H, s), 7.67 (1H, d, J = 7.3 Hz), 7.62- 7.58 (2H, br m), 7.45 (1H, s), 7.28 (1H, dd, J = 8.5, 1.8 Hz), 7.14 (1H, d, J = 11.0 Hz), 6.99 (2H, br s), 3.68 (2H, s), 2.53 (3H, s), 2.52-2.45 (4H, m), 1.72-1.67 (4H, m).
- 107 107
- ■oo [5-amino-1-(2-metil-1H- bencimidazol-5-il)- 1Hpirazol- 4-il] -[6-(1- metilpiperidin-4-il)-1 H- indol-2-il]-metanona 454 1H-RMN (DMSO-D6) 8: 12.47 (1H, s), 11.56 (1H, s), 8.28 (1H, s), 7.63-7.57 (2H, br m), 7.60 (1H, d, J = 8.5 Hz), 7.39 (1H, d, J = 1.8 Hz), 7.30 (1H, s), 7.28 (1H, dd, J = 8.5, 1.8 Hz), 6.99 (1H, dd, J = 8.5, 1.8 Hz), 6.98 (2H, br s), 2.91-2.86 (2H, br m), 2.55-2.51 (1H, br m), 2.53 (3H, s), 2.20 (3H, s), 2.02-1.96 (2H, m), 1.79-1.64 (4H, m). ■ oo [5-amino-1- (2-methyl-1H- benzimidazol-5-yl) -1Hpirazol-4-yl] - [6- (1- methylpiperidin-4-yl) -1 H- indole-2- il] -methanone 454 1H-NMR (DMSO-D6) 8: 12.47 (1H, s), 11.56 (1H, s), 8.28 (1H, s), 7.63-7.57 (2H, br m), 7.60 (1H, d, J = 8.5 Hz), 7.39 (1H, d, J = 1.8 Hz), 7.30 (1H, s), 7.28 (1H, dd, J = 8.5, 1.8 Hz), 6.99 (1H, dd, J = 8.5 , 1.8 Hz), 6.98 (2H, br s), 2.91-2.86 (2H, br m), 2.55-2.51 (1H, br m), 2.53 (3H, s), 2.20 (3H, s), 2.02-1.96 (2H, m), 1.79-1.64 (4H, m).
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 108 108
- [5-amino-1-(2-metil-1 H- bencimidazol-5-il)- 1 Hpirazol-4-il] -[6-(4- morfolin-4-il-fenil)-1 H- indol-2-il]-metanona 518 1H-RMN (DMSO-D6) 8: 12.47 (1H, s), 11.69 (1H, s), 8.32 (1H, d, J = 1.8 Hz), 7.73 (1H, d, J=6.7 Hz), 7.64-7.56 (5H, m), 7.46 (1H, s), 7.37 (1H, d, J = 8.5 Hz), 7.30 (1H, d, J = 8.5 Hz), 7.09-6.97 (4H,m), 3.80-3.73 (4H, m), 3.19-3.14 (4H, m), 2.53 (3H, s). [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 Hpirazol-4-yl] - [6- (4- morpholin-4-yl-phenyl) -1 H- indole- 2-yl] -methanone 518 1H-NMR (DMSO-D6) 8: 12.47 (1H, s), 11.69 (1H, s), 8.32 (1H, d, J = 1.8 Hz), 7.73 (1H, d, J = 6.7 Hz), 7.64-7.56 (5H, m), 7.46 (1H, s), 7.37 (1H, d, J = 8.5 Hz), 7.30 (1H, d, J = 8.5 Hz), 7.09-6.97 (4H , m), 3.80-3.73 (4H, m), 3.19-3.14 (4H, m), 2.53 (3H, s).
- 109 109
- [5-amino-1-(2-metil-1 H- bencimidazol- 5-il)- 1 Hpirazol-4-il] -[6- (3,4,5,6- tetrahidro-2H- [1,2'] bipi ridin-5'-il)-1H- indol-2-il]-metanona 517 1H-RMN (DMSO-D6) 8: 11.70 (1H, s), 8.45 (1H, d, J = 2.4 Hz), 8.33 (1H, s), 7.83 (1H, dd, J = 8.9, 2.7 Hz), 7.74 (1H, d, J = 8.5 Hz), 7.64-7.59 (4H, d, J = 8.5 Hz), 7.47 (1H, s), 7.36 (1H, d, J = 8.5 Hz), 7.30 (1H, dd, J = 8.5, 1.8 Hz), 7.01 (2H, s), 6.92 (1H, d, J = 9.2 Hz), 3.58 (4H, t, J = 5.2 Hz), 2.54 (3H, s), 1.641.57 (6H, m). [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 Hpirazol-4-yl] - [6- (3,4,5,6-tetrahydro-2H- [1,2 '] bipi ridin-5'-il) -1H- indole-2-yl] -methanone 517 1H-NMR (DMSO-D6) 8: 11.70 (1H, s), 8.45 (1H, d, J = 2.4 Hz) , 8.33 (1H, s), 7.83 (1H, dd, J = 8.9, 2.7 Hz), 7.74 (1H, d, J = 8.5 Hz), 7.64-7.59 (4H, d, J = 8.5 Hz), 7.47 ( 1H, s), 7.36 (1H, d, J = 8.5 Hz), 7.30 (1H, dd, J = 8.5, 1.8 Hz), 7.01 (2H, s), 6.92 (1H, d, J = 9.2 Hz), 3.58 (4H, t, J = 5.2 Hz), 2.54 (3H, s), 1,641.57 (6H, m).
- 110 110
- [5-amino-1-(2-metil-1 H- bencimidazol-5-il)- 1Hpirazol- 4-il] -[6-(6- piperazin-1 -il-piridin-3- il)- 1 H-indol-2-il]- metanona 518 1H-RMN (DMSO-D6) 8: 12.47 (1H, s), 11.71 (1H, s), 8.46 (1H, d, J = 2.4 Hz), 8.33 (1H, s), 7.85 (1H, dd, J = 8.5, 2.4 Hz), 7.75 (1H, d, J = 8.5 Hz), 7.65-7.58 (3H, m), 7.47 (1H, s), 7.36 (1H, d, J =7.9 Hz), 7.30 (1H, dd, J =8.5, 1.8 Hz), 7.01 (2H, s), 6.91 (1H, d, J = 9.2 Hz), 3.46 (4H, t, J = 4.9 Hz), 2.80 (4H, t, J = 4.9 Hz), 2.54 (3H, s). [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1Hpirazol-4-yl] - [6- (6- piperazin-1-yl-pyridin-3- yl) - 1 H -indole-2-yl] - methanone 518 1H-NMR (DMSO-D6) 8: 12.47 (1H, s), 11.71 (1H, s), 8.46 (1H, d, J = 2.4 Hz), 8.33 (1H, s), 7.85 (1H, dd, J = 8.5, 2.4 Hz), 7.75 (1H, d, J = 8.5 Hz), 7.65-7.58 (3H, m), 7.47 (1H, s), 7.36 (1H, d , J = 7.9 Hz), 7.30 (1H, dd, J = 8.5, 1.8 Hz), 7.01 (2H, s), 6.91 (1H, d, J = 9.2 Hz), 3.46 (4H, t, J = 4.9 Hz ), 2.80 (4H, t, J = 4.9 Hz), 2.54 (3H, s).
- 111 111
- JHi [5-amino-1-(2-metil-1 H- bencimidazol-5-il)- 1 Hpirazol-4-il] -[5-(6- metoxi-piridin-3-il)-1 H- indol- 2-il]-metanona 464 1H-RMN (DMSO-D6) 8: 12.47 (1H, s), 11.79 (1H, s), 8.49 (1H, d, J = 2.4 Hz), 8.32 (1H, s), 8.03 (1H, dd, J = 8.9, 2.7 Hz), 7.93 (1H, s), 7.62-7.54 (4H, m), 7.49 (1H, s), 7.30 (1H, dd, J = 8.2, 2.1 Hz), 7.02 (2H, s), 6.92 (1H, d, J = 9.2 Hz), 3.91 (3H, s), 2.54 (3H, s). JHi [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 Hpirazol-4-yl] - [5- (6- methoxy-pyridin-3-yl) -1 H- indole - 2-yl] -methanone 464 1H-NMR (DMSO-D6) 8: 12.47 (1H, s), 11.79 (1H, s), 8.49 (1H, d, J = 2.4 Hz), 8.32 (1H, s) , 8.03 (1H, dd, J = 8.9, 2.7 Hz), 7.93 (1H, s), 7.62-7.54 (4H, m), 7.49 (1H, s), 7.30 (1H, dd, J = 8.2, 2.1 Hz ), 7.02 (2H, s), 6.92 (1H, d, J = 9.2 Hz), 3.91 (3H, s), 2.54 (3H, s).
- 112 112
- n ■> NH. /* F'T^ n -Ct1* [5-amino-1-(2-metil-1 H- bencimidazol-5-il)- 1Hpirazol- 4-il] -[5-((S)- 3-metil-morfolin-4- ilmetil)-1 H-indol-2-il]- metanona 470 1H-RMN (DMSO-D6) 8: 12.46 (1H, s), 11.65 (1H, s), 8.30 (1H, s), 7.60-7.58 (3H, m), 7.44-7.42 (2H, m), 7.30 (1H, d, J = 8.5 Hz), 7.22 (1H, d, J = 8.5 Hz), 6.99 (2H, s), 4.08 (1H, d, J = 12.8 Hz), 3.64-3.61 (2H, m), 3.43-3.40 (2H, m), 3.17-3.14 (2H, m), 2.53 (3H, s), 2.422.40 (1H, m), 2.12-2.08 (1H, m), 1.06 (3H, d, J = 6.7 Hz). n ■> NH. / * F'T ^ n -Ct1 * [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) - 1 Hpirazol-4-yl] - [5 - ((S) - 3-methyl -morpholin-4-ylmethyl) -1 H-indol-2-yl] - methanone 470 1 H-NMR (DMSO-D6) 8: 12.46 (1H, s), 11.65 (1H, s), 8.30 (1H, s) , 7.60-7.58 (3H, m), 7.44-7.42 (2H, m), 7.30 (1H, d, J = 8.5 Hz), 7.22 (1H, d, J = 8.5 Hz), 6.99 (2H, s), 4.08 (1H, d, J = 12.8 Hz), 3.64-3.61 (2H, m), 3.43-3.40 (2H, m), 3.17-3.14 (2H, m), 2.53 (3H, s), 2,422.40 ( 1H, m), 2.12-2.08 (1H, m), 1.06 (3H, d, J = 6.7 Hz).
- 113 113
- H rt oxtH,", * VvW M [5-amino-1-(2-metil-1 H- bencimidazol-5-il)- 1Hpirazol- 4-il] -[6-((R)- 3- fluoro-pirrolidin-1- ilmetil)-1 H-indol-1-il]- metanona 458 1H-MMR (DMSO-D6) 8: 12.48 (1H, s), 11.64 (1H, s), 8.29 (1H, s), 7.61-7.58 (3H, m), 7.42-7.40 (2H, m), 7.28 (1H, dd, J = 8.5, 2.1 Hz), 7.04 (1H, dd, J = 8.2, 1.2 Hz), 6.98 (2H, br s), 5.28-5.11 (1H, m), 3.68 (2H, s), 2.82-2.75 (2H, m), 2.67-2.65 (1H. m), 2.52 (3H, s), 2.32-2.30 (1H, m), 2.20-2.08 (1H, m), 1.94-1.78 (1H, m). H rt oxtH, ", * VvW M [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) - 1 Hpirazol-4-yl] - [6 - ((R) - 3- fluoro- pyrrolidin-1-ylmethyl) -1 H-indol-1-yl] -methanone 458 1H-MMR (DMSO-D6) 8: 12.48 (1H, s), 11.64 (1H, s), 8.29 (1H, s), 7.61-7.58 (3H, m), 7.42-7.40 (2H, m), 7.28 (1H, dd, J = 8.5, 2.1 Hz), 7.04 (1H, dd, J = 8.2, 1.2 Hz), 6.98 (2H, br s), 5.28-5.11 (1H, m), 3.68 (2H, s), 2.82-2.75 (2H, m), 2.67-2.65 (1H. m), 2.52 (3H, s), 2.32-2.30 (1H , m), 2.20-2.08 (1H, m), 1.94-1.78 (1H, m).
114114
[5-amino-1-(2-metil)- 1 H-bencimidazol-5-il)- 1Hpirazol- 4-il] -[5-(2,5- dimetil-pirrolidin-1- ilmetil)-1 H-indol-2-il]- metanona[5-amino-1- (2-methyl) - 1 H -benzimidazol-5-yl) -1Hpyrazol-4-yl] - [5- (2,5-dimethyl-pyrrolidin-1- ylmethyl) -1 H- indole-2-il] - methanone
468468
1H-RMN (DMSO-D6) 8: 12.44 (1H, d, J = 4.3 Hz), 11.60 (1H, s), 8.30 (1H, d, J = 4.3 Hz), 7.65-7.55 (3H, m), 7.417.40 (2H, m), 7.28-7.21 (2H, m), 6.98 (2H, d. J = 22.0 Hz), 3.90-3.52 (2H, m), 2.97-2.95 (1H, m), 2.61 (1H, dd, J = 11.0, 5.5 Hz), 2.53 (3H, s), 1.99-1.93 (1H, m), 1.80-1.74 (1H, m), 1.32-1.27 (2H, m), 0.97 (6H, t, J = 6.1 Hz).1H-NMR (DMSO-D6) 8: 12.44 (1H, d, J = 4.3 Hz), 11.60 (1H, s), 8.30 (1H, d, J = 4.3 Hz), 7.65-7.55 (3H, m), 7,417.40 (2H, m), 7.28-7.21 (2H, m), 6.98 (2H, d. J = 22.0 Hz), 3.90-3.52 (2H, m), 2.97-2.95 (1H, m), 2.61 ( 1H, dd, J = 11.0, 5.5 Hz), 2.53 (3H, s), 1.99-1.93 (1H, m), 1.80-1.74 (1H, m), 1.32-1.27 (2H, m), 0.97 (6H, t, J = 6.1 Hz).
115115
[5-amino-1-(2-metil-1 H- bencimidazol-5-il)- 1 Hpirazol-4-il] -[5-(3- fluoropiperidin- 1-ilmetil) -1 H-indol-2-il]- metanona[5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 Hpirazol-4-yl] - [5- (3- fluoropiperidin-1-ylmethyl) -1 H-indole-2- il] - methanone
472472
1H-RMN (DMSO-D6) 8: 12.45 (1H, s), 11.64 (1H, s), 8.29 (1H, s), 7.63-7.56 (3H, m), 7.44-7.41 (2H, m), 7.29 (1H, d, J = 8.5 Hz), 7.20 (1H, d, J = 8.5 Hz), 6.98 (2H, s), 4.62 (1H, d, d = 48.2 Hz), 3.57 (2H, s), 2.75-2.21 (4H, m), 2.53 (3H, s), 1.80-1.74 (2H, m), 1.52-1.43 (2H, m).1H-NMR (DMSO-D6) 8: 12.45 (1H, s), 11.64 (1H, s), 8.29 (1H, s), 7.63-7.56 (3H, m), 7.44-7.41 (2H, m), 7.29 (1H, d, J = 8.5 Hz), 7.20 (1H, d, J = 8.5 Hz), 6.98 (2H, s), 4.62 (1H, d, d = 48.2 Hz), 3.57 (2H, s), 2.75 -2.21 (4H, m), 2.53 (3H, s), 1.80-1.74 (2H, m), 1.52-1.43 (2H, m).
116116
[5-amino-1-(2-metil-1 H- bencimidazol-5-il)- 1 Hpirazol-4-il] -[5-(3,3- difluoro-piperidin-1- ilmetil)-1 H-indol-2-il]- metanona[5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 Hpirazol-4-yl] - [5- (3,3-difluoro-piperidin-1- ylmethyl) -1 H- indole-2-il] - methanone
490490
1H-RMN (DMSO-D6) 8: 12.46 (1H, s), 11.66 (1H, s), 8.30 (1H, s), 7.61-7.58 (3H, m), 7.45-7.42 (2H, m), 7.29 1H, dd, J = 8.5, 1.8 Hz), 7.20 (1H, d, J = 8.5 Hz), 6.99 (2H, s), 3.64 (2H. s), 2.59-2.51 (4H, m), 2.53 (3H, s), 1.881.86 (2H, m), 1.66-1.64 (2H, m).1H-NMR (DMSO-D6) 8: 12.46 (1H, s), 11.66 (1H, s), 8.30 (1H, s), 7.61-7.58 (3H, m), 7.45-7.42 (2H, m), 7.29 1H, dd, J = 8.5, 1.8 Hz), 7.20 (1H, d, J = 8.5 Hz), 6.99 (2H, s), 3.64 (2H. S), 2.59-2.51 (4H, m), 2.53 (3H , s), 1881.86 (2H, m), 1.66-1.64 (2H, m).
117117
[5-amino-1-(2-metil-1 H- bencimidazol-5-il)- 1 Hpirazol-4-il] -{6-[2-(4- metil-piperazin-1-il) piridin-4-il]-1 H-indol-2- il}-metanona[5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 Hpirazol-4-yl] - {6- [2- (4- methyl-piperazin-1-yl) pyridin-4 -il] -1 H-indole-2-yl} -methanone
532532
1H-RMN (DMSO-D6) 8: 12.47 (1H, s), 11.72 (1H, d, J = 1.2 Hz), 8.45 (1H,d, J = 3.1 Hz), 8.33 (1H, s), 7.86 (1H, dd, J =8.9, 2.1 Hz 7.75 (1H, d, J = 8.5 Hz), 7.68-7.55 (3H, m), 7.48 (1H, d, J = 1.2 Hz), 7.36 (1H, dd, J = 8.2, 1.5 Hz), 7.30 (1H, d, J = 7.9 Hz), 7.07-6.93 (3H, dd, m), 3.57-3.52 (4H, m), 2.53 (3H, s), 2.44-2.39 (4H, m), 2.23 (3H,1H-NMR (DMSO-D6) 8: 12.47 (1H, s), 11.72 (1H, d, J = 1.2 Hz), 8.45 (1H, d, J = 3.1 Hz), 8.33 (1H, s), 7.86 ( 1H, dd, J = 8.9, 2.1 Hz 7.75 (1H, d, J = 8.5 Hz), 7.68-7.55 (3H, m), 7.48 (1H, d, J = 1.2 Hz), 7.36 (1H, dd, J = 8.2, 1.5 Hz), 7.30 (1H, d, J = 7.9 Hz), 7.07-6.93 (3H, dd, m), 3.57-3.52 (4H, m), 2.53 (3H, s), 2.44-2.39 ( 4H, m), 2.23 (3H,
s).s).
118118
[5-amino-1-(2-metil-1 H- bencimidazol-5-il)- 1Hpyrazol- 4-il] -(6- piridin-4-il-1 H-indol-2- il)- ' metanona[5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1Hpyrazol-4-yl] - (6- pyridin-4-yl-1 H-indol-2- yl) - 'methanone
434434
1H-RMN (DMSO-D6) 8: 8.66 (2H, dd, J = 4.6, 1.5 Hz), 8.34 (1H, s), 7.84 (2H, d, J = 9.2 Hz), 7.72 (2H, dd, J = 4.6, 1.5 Hz), 7.61 [2H, t, J = 4.6 Hz), 7.55-7.50 (2H, m), 7.29 (1H, dd, J = 8.2, 2.1 Hz), 7.06 (2H, s), 2.55 (3H, s).1H-NMR (DMSO-D6) 8: 8.66 (2H, dd, J = 4.6, 1.5 Hz), 8.34 (1H, s), 7.84 (2H, d, J = 9.2 Hz), 7.72 (2H, dd, J = 4.6, 1.5 Hz), 7.61 [2H, t, J = 4.6 Hz), 7.55-7.50 (2H, m), 7.29 (1H, dd, J = 8.2, 2.1 Hz), 7.06 (2H, s), 2.55 (3H, s).
119119
[5-amino-1-(2-metil-1 H- bencimidazol-5-il)- 1Hpirazol- 4-ill -[5-(4- fluoropiperidi n-1- ilmetil)- 1 H-indol-2-il]- metanona[5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1Hpirazol-4-ill - [5- (4- fluoropiperidi n-1- ylmethyl) - 1 H-indole-2-yl ] - methanone
472472
1H-RMN (DMSO-D6) 8: 12.46 (1H, d, J = 4.9 Hz), 11.66 (1H, d, J = 1.8 Hz), 8.30 (4H, d. J = 4.9 Hz), 7.65 (1H, dd, J = 5.2, 3.4 Hz), 7.58-7.56 (2H, m), 7.44-7.42 (2H, m), 7.32-7.27 (1H, m), 7.21 (1H, d, J = 4.9 Hz), 7.00 (2H, d, J = 22.6 Hz), 4.72-4.65 (1H, m), 3.54 (2H, s), 2.53 (3H, s), 2.51-2.48 (2H, m), 2.32-2.31 (2H, m), 1.89-1.83 (2H, m), 1.73-1.71 (2H, m).1H-NMR (DMSO-D6) 8: 12.46 (1H, d, J = 4.9 Hz), 11.66 (1H, d, J = 1.8 Hz), 8.30 (4H, d. J = 4.9 Hz), 7.65 (1H, dd, J = 5.2, 3.4 Hz), 7.58-7.56 (2H, m), 7.44-7.42 (2H, m), 7.32-7.27 (1H, m), 7.21 (1H, d, J = 4.9 Hz), 7.00 (2H, d, J = 22.6 Hz), 4.72-4.65 (1H, m), 3.54 (2H, s), 2.53 (3H, s), 2.51-2.48 (2H, m), 2.32-2.31 (2H, m ), 1.89-1.83 (2H, m), 1.73-1.71 (2H, m).
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 120 120
- ÍO-^ [5-amino-1-(2-metil-1 H- bencimidazol-5-il)- 1 Hpirazol-4-il] -[5-(4,4- difluoro-pi peridi n-1- ilmetil)-1 H-indol-2-il]- metanona 490 1H-RMN (DMSO-D6) 8: 12.45 (1H, s), 11.66 (1H, s), 8.29 (1H, s), 7.617.58 (3H, m), 7.43-7.42 (2H, m), 7.29 (1H, dd, J = 8.4, 2.1 Hz), 7.22 (1H, dd, J = 8.4, 1.8 Hz), 6.99 (2H, s), 3.61 (2H, s), 3.34-3.30 (4H, m), 2.53 (3H, s), 1.99-1.90 (4H, m). ÍO- ^ [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) - 1 Hpirazol-4-yl] - [5- (4,4- difluoro-pi peridi n-1- ilmethyl ) -1 H-indole-2-yl] - methanone 490 1H-NMR (DMSO-D6) 8: 12.45 (1H, s), 11.66 (1H, s), 8.29 (1H, s), 7.617.58 (3H , m), 7.43-7.42 (2H, m), 7.29 (1H, dd, J = 8.4, 2.1 Hz), 7.22 (1H, dd, J = 8.4, 1.8 Hz), 6.99 (2H, s), 3.61 ( 2H, s), 3.34-3.30 (4H, m), 2.53 (3H, s), 1.99-1.90 (4H, m).
- 121 121
- [5-amino-1-(2- difluorometil-1H- bencimidazol-5-il)- 1IIpirazol- 4-il] -[5-(1- metilpiperidin- 4-il)-1H- indol-2-il]-metanona 490 1H-RMN (DMSO-D6) 8: 13.60 (1H, br s), 11.58 (1H, d, J = 1.8 Hz), 8.31 (1H, s), 7.83-7.80 (2H, m), 7.51-7.46 (2H, m), 7.45-7.38 (2H, m), 7.327.14 (2H, br m), 7.08 (2H, br s), 2.93-2.85 (2H, m), 2.56-2.50 (1H, m), 2.21 (3H, s), 2.04-1.96 (2H, m), 1.81-1.65 (4H, br m). [5-amino-1- (2- difluoromethyl-1H- benzimidazol-5-yl) - 1IIpyrazol-4-yl] - [5- (1- methylpiperidin-4-yl) -1H- indole-2-yl] - methanone 490 1H-NMR (DMSO-D6) 8: 13.60 (1H, br s), 11.58 (1H, d, J = 1.8 Hz), 8.31 (1H, s), 7.83-7.80 (2H, m), 7.51- 7.46 (2H, m), 7.45-7.38 (2H, m), 7.327.14 (2H, br m), 7.08 (2H, br s), 2.93-2.85 (2H, m), 2.56-2.50 (1H, m ), 2.21 (3H, s), 2.04-1.96 (2H, m), 1.81-1.65 (4H, br m).
- 122 122
- [5-amino-1-(2- difluorometil-1H- bencimidazol-5-il)- 1Hpirazol- 4-il] -(1H- indol-2-il)-metanona 393 1H-RMN (DMSO-D6) 8: 13.60 (1H, br s), 11.69 (1H, s), 8.34 (1H, s), 7.84-7.80 (2H, m), 7.70 (1H, d, J = 7.9 Hz), 7.51-7.45 (3H, m), 7.32-7.19 (2H, m), 7.12-7.06 (3H, m). [5-amino-1- (2- difluoromethyl-1H- benzimidazol-5-yl) -1Hpirazol-4-yl] - (1H- indole-2-yl) -methanone 393 1 H-NMR (DMSO-D6) 8: 13.60 (1H, br s), 11.69 (1H, s), 8.34 (1H, s), 7.84-7.80 (2H, m), 7.70 (1H, d, J = 7.9 Hz), 7.51-7.45 (3H, m ), 7.32-7.19 (2H, m), 7.12-7.06 (3H, m).
- 123 123
- k í j'Y [5-amino-1-(2-metil-1 H- bencimidazol-5-il)- 1Hpirazol- 4-il] -[5-(3,3- difluoro-pirrolidin-1- ilmetil)-1 H-indol-2-il]- metanona 476 1H-RMN (DMSO-D6) 8: 12.47 (1H, s), 11.68 (1H, s), 8.30 (1H, d, J = 4.9 Hz), 7.65 (1H, dd, J = 5.0, 3.4 Hz), 7.61-7.55 (2H, m), 7.47-7.41 (2H, m), 7.30 (1H, t, J = 6.4 Hz), 7.22 (1H, d, J = 8.5 Hz), 7.00 (2H, d, J = 21.4 Hz), 3.69 (2H, s), 2.86 (2H, t, J = 13.5 Hz), 2.66-2.42 (2H, m), 2.61 (3H, s), 2.29-2.22 (2H, m) k í j'Y [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1Hpirazol-4-yl] - [5- (3,3-difluoro-pyrrolidin-1- ylmethyl) -1 H-indole-2-yl] - methanone 476 1H-NMR (DMSO-D6) 8: 12.47 (1H, s), 11.68 (1H, s), 8.30 (1H, d, J = 4.9 Hz), 7.65 (1H, dd, J = 5.0, 3.4 Hz), 7.61-7.55 (2H, m), 7.47-7.41 (2H, m), 7.30 (1H, t, J = 6.4 Hz), 7.22 (1H, d, J = 8.5 Hz), 7.00 (2H, d, J = 21.4 Hz), 3.69 (2H, s), 2.86 (2H, t, J = 13.5 Hz), 2.66-2.42 (2H, m), 2.61 (3H, s ), 2.29-2.22 (2H, m)
- 124 124
- [5-amino-1-(2-metil-1 H- bencimidazol- 5-il)- 1Hpirazol- 4-il] -[5-(1- ciclopentil-piperidin-4-il)- 1 H-indol-2-il]-metanona 508 1H-RMN (DMSO-D6) 8:12.47 (1H, s), 11.57 (1H, d, J = 1.2 Hz), 8.29 (1H, d, J = 3.7 Hz), 7.66-7.56 (2H, m), 7.50 (1H, s), 7.43-7.37 (2H, m), 7.29 (1H, t, J = 6.1 Hz), 7.17 (1H, dd, J = 8.5, 1.2 Hz), 6.99 (2H, d, J = 22.0 Hz), 3.06 (2H, d, J = 11.0 Hz), 2.54 (3H, s), 2.02 (2H, t, J = 10.7 Hz), 1.64-1.48 (14H, m). [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1Hpirazol-4-yl] - [5- (1- cyclopentyl-piperidin-4-yl) - 1 H-indole-2 -il] -methanone 508 1H-NMR (DMSO-D6) 8: 12.47 (1H, s), 11.57 (1H, d, J = 1.2 Hz), 8.29 (1H, d, J = 3.7 Hz), 7.66-7.56 (2H, m), 7.50 (1H, s), 7.43-7.37 (2H, m), 7.29 (1H, t, J = 6.1 Hz), 7.17 (1H, dd, J = 8.5, 1.2 Hz), 6.99 ( 2H, d, J = 22.0 Hz), 3.06 (2H, d, J = 11.0 Hz), 2.54 (3H, s), 2.02 (2H, t, J = 10.7 Hz), 1.64-1.48 (14H, m).
- 125 125
- [5-amino-1-(2-metil-1 H- bencimidazol- 5-il)- 1Hpirazol- 4-il] -[5-(1- ciclohexil-piperidin-4-il)- 1 H-indol-2-il]-metanona 522 1H-RMN (DMSO-D6) 8: 12.46 (1H, s), 11.57 (1H, d, J = 1.8 Hz), 8.29 (1H, s), 7.62-7.58 (2H, m), 7.49 (1H, s), 7.40-7.37 (2H, m), 7.29 (1H, d, J = 7.9 Hz), 7.16 (1H, dd, J = 8.5, 1.2 Hz), 6.98 (2H, d. J = 20.8 Hz), 2.93 (2H, d, J = 11.6 Hz), 2.53 (3H, s), 2.36-2.31 (3H, m), 1.80-1.57 (9H, m), 1.22-1.14 (6H, m). [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1Hpirazol-4-yl] - [5- (1- cyclohexyl-piperidin-4-yl) - 1 H-indole-2 -il] -methanone 522 1H-NMR (DMSO-D6) 8: 12.46 (1H, s), 11.57 (1H, d, J = 1.8 Hz), 8.29 (1H, s), 7.62-7.58 (2H, m) , 7.49 (1H, s), 7.40-7.37 (2H, m), 7.29 (1H, d, J = 7.9 Hz), 7.16 (1H, dd, J = 8.5, 1.2 Hz), 6.98 (2H, d. J = 20.8 Hz), 2.93 (2H, d, J = 11.6 Hz), 2.53 (3H, s), 2.36-2.31 (3H, m), 1.80-1.57 (9H, m), 1.22-1.14 (6H, m) .
- 126 126
- [5-amino-1-(2-metil-1 H- bencimidazol-5-il)- 1Hpirazol- 4-il] -(4- bromo-1Hpirrol- 2-il)- metanona 385, 387 1H-RMN (DMSO-D6) 8: 12.47 (1H, s), 12.04 (1H, s), 12.04 (1H, s), 8.20 (1H, s), 7.61-7.57 (1H, m), 7.27 (1H, dd, J = 8.5, 1.7 Hz), 7.19-7.18 (2H, m), 6.93-6.90 (3H, m), 2.53 (3H, s). [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1Hpirazol-4-yl] - (4- bromo-1Hpirrol-2-yl) - methanone 385, 387 1H-NMR (DMSO -D6) 8: 12.47 (1H, s), 12.04 (1H, s), 12.04 (1H, s), 8.20 (1H, s), 7.61-7.57 (1H, m), 7.27 (1H, dd, J = 8.5, 1.7 Hz), 7.19-7.18 (2H, m), 6.93-6.90 (3H, m), 2.53 (3H, s).
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 127 127
- [5-amino-1-(2-met¡l- lllbenclmidazol- 5-11)- 1 Hpirazol- 4-il] -(1H- plrrol-2-ll)-metanona 307 1H-RMN (DMSO-D6) 8: 12.46 (1H, s), 11.71 (1H, s), 8.16 (1H, d, J = 3.0 Hz), 7.59 (2H, dd, J = 23.6, 7.1 Hz), 7.29 (1H, d, J = 10.0 Hz), 7.08 (1H, d, J = 15.4 Hz), 6.85 (2H, d, J = 14.8 Hz), 6.24-6.22 (2H, m), 2.53 (3H, s). [5-amino-1- (2-methyl-lllbenclmidazole-5-11) - 1 Hpirazol-4-yl] - (1H- plrrol-2-ll) -methanone 307 1H-NMR (DMSO-D6) 8 : 12.46 (1H, s), 11.71 (1H, s), 8.16 (1H, d, J = 3.0 Hz), 7.59 (2H, dd, J = 23.6, 7.1 Hz), 7.29 (1H, d, J = 10.0 Hz), 7.08 (1H, d, J = 15.4 Hz), 6.85 (2H, d, J = 14.8 Hz), 6.24-6.22 (2H, m), 2.53 (3H, s).
- 128 128
- [5-amlno-1-(2-metll-1 H- benclmldazol- 5-II)- 1 Hpirazol- 4-il] -(4-fenil- IHpirrol- 2-¡l)-metanona 383 1H-RMN (CD30D) 8: 8.54 (1H, s), 8.25 (1H, s), 7.94 (1H, d, J = 1.5 Hz), 7.91 (1H, d, J = 1.8 Hz), 7.67-7.63 (2H, m), 7.44-7.31 (5H, m), 2.61 (3H, s)- [5-amlno-1- (2-metll-1 H- benclmldazol-5-II) - 1 Hpirazol-4-yl] - (4-phenyl- IHpirrol- 2-¡l) -methanone 383 1H-NMR (CD30D ) 8: 8.54 (1H, s), 8.25 (1H, s), 7.94 (1H, d, J = 1.5 Hz), 7.91 (1H, d, J = 1.8 Hz), 7.67-7.63 (2H, m), 7.44-7.31 (5H, m), 2.61 (3H, s) -
- 129 129
- te 0- ? "Xtr [5-amino-1-(2-metll-1 H- bencimidazol- 5-II)- 1 Hpirazol- 4-il] -[4-(3- clorofenil)-1 H-p¡ rrol-2-il]- metanona 417 1H-RMN (CD30D) 5: 8.30-8.26 (1H, m), 7.66 (2H, dt, J = 5.4, 2.4 Hz), 7.58 (1H, dq, J = 7.8, 0.9 Hz), 7.48 (1H, d, J = 1.6 Hz), 7.42 (1H, d, J = 1.5 Hz), 7.39 (1H, d, J = 2.0 Hz), 7.36 (1H, d, J = 1.8 Hz), 7.31 (1H, d, J = 7.9 Hz), 7.17 (1H, dq, J = 8.0, 1.0 Hz), 2.61 (3H, s). you 0-? "Xtr [5-amino-1- (2-metll-1 H- benzimidazol-5-II) - 1 Hpirazol-4-yl] - [4- (3- chlorophenyl) -1 Hp¡rol-2-yl] - methanone 417 1H-NMR (CD30D) 5: 8.30-8.26 (1H, m), 7.66 (2H, dt, J = 5.4, 2.4 Hz), 7.58 (1H, dq, J = 7.8, 0.9 Hz), 7.48 ( 1H, d, J = 1.6 Hz), 7.42 (1H, d, J = 1.5 Hz), 7.39 (1H, d, J = 2.0 Hz), 7.36 (1H, d, J = 1.8 Hz), 7.31 (1H, d, J = 7.9 Hz), 7.17 (1H, dq, J = 8.0, 1.0 Hz), 2.61 (3H, s).
- 130 130
- G j IJH. F [5-amino-1-(2-met¡l-1 H- bencimidazol- 5-¡l)- 1 Hpirazol- 4-il] -[4-(4- fluorofenil)-1 H-pi rrol-2- ¡l]-metanona 401 1H-RMN (CD30D) 8: 8.26 (1H, s), 7.66-7.63 (3H. m), 7.40 (1H, dd, J = 3.7, 1.7 Hz), 7.36 (1H, dd, J = 3.0, 1.8 Hz), 7.11 (1H, d, J = 2.1 Hz), 7.08 (2H, t, J = 2.1 Hz), 7.05 (1H, d, J =2.1 Hz), 2.61 (3H, s). G j IJH. F [5-amino-1- (2-methyl-1 H- benzimidazol-5-l) - 1 Hpirazol-4-yl] - [4- (4- fluorophenyl) -1 H-pi rrol-2 - l] -methanone 401 1H-NMR (CD30D) 8: 8.26 (1H, s), 7.66-7.63 (3H. M), 7.40 (1H, dd, J = 3.7, 1.7 Hz), 7.36 (1H, dd , J = 3.0, 1.8 Hz), 7.11 (1H, d, J = 2.1 Hz), 7.08 (2H, t, J = 2.1 Hz), 7.05 (1H, d, J = 2.1 Hz), 2.61 (3H, s ).
- 131 131
- H [5-amino-1-(2-met¡l-1 H- bencimidazol- 5-il)- 1 Hpirazol- 4-vl] -[4-(- fluorofenil)-1 H-pi rrol-2- il]-metanona 401 1H-RMN (CD30D) 8: 8.27 (1H, s), 7.66-7.65 (2H, m), 7.47 (1H, d, J = 1.5 Hz), 7.45 (1H, t, J = 1.2 Hz), 7.42 (1H, d, J = 1.6 Hz). 7.39-7.35 (2H, m), 7.33-7.31 (1H, m), 6.94-6.86 (1H, m), 2.61 (3H, s). H [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 Hpirazol-4-vl] - [4 - (- fluorophenyl) -1 H-pi rrol-2- il ] -methanone 401 1H-NMR (CD30D) 8: 8.27 (1H, s), 7.66-7.65 (2H, m), 7.47 (1H, d, J = 1.5 Hz), 7.45 (1H, t, J = 1.2 Hz ), 7.42 (1H, d, J = 1.6 Hz). 7.39-7.35 (2H, m), 7.33-7.31 (1H, m), 6.94-6.86 (1H, m), 2.61 (3H, s).
[Ejemplo 132: Síntesis de [5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(6-morfolin-4-ilmetil-1H-¡ndol-2- il)-metanona][Example 132: Synthesis of [5-amino-1- (2-methyl-1H-benzyldazol-5-α) -1H-pyrolol-4-α] - (6-morpholin -4-ilmethyl-1H-¡ndol-2- il) -methanone]
rr
o.or.
nn
HH
.. -N o.. -No
■■
NH? NNH? N
NN
JLJL
NN
NN
HH
5 La [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(1-bencenosulfon¡l-6-morfolin-4-¡lmet¡l - 1H-indol-2-il)- metanona (132 mg, 0.22 mmol) se disolvió en tetrahidrofurano (THF) (1.0 mi), y a continuación, se le adicionó una solución en tetrahidrofurano (THF) de fluoruro de tetrabutilamonio 1M (0.46 mi, 0.46 mmol). La mezcla se calentó a 65°C con agitación, durante 22 horas. A continuación, la mezcla de reacción se enfrió a temperatura ambiente, y se concentró bajo presión reducida. El residuo resultante se purificó por cromatografía de columna de sílica gel 10 (dlclorometano/metanol = 100/10) para dar la [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-pirazol-4-¡l]-(6-morfol¡n-4- ilmetil-1 Hin dol-2-ll)-metanona como un sólido de color amarillo (74 mg, 75%).5 La [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1 H-prazol-4-l] - (1-benzenesulfonyl) -6-morpholin-4-lmetl-1H-indole-2-yl) -methanone (132 mg, 0.22 mmol) was dissolved in tetrahydrofuran (THF) (1.0 ml), and then a solution was added in tetrahydrofuran (THF) of 1M tetrabutylammonium fluoride (0.46 ml, 0.46 mmol). The mixture was heated at 65 ° C with stirring, for 22 hours. Then, the reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography 10 (dichloromethane / methanol = 100/10) to give [5-amine-1- (2-methyl-1H-benzyldazol-5 -¡L) -1H-pyrazol-4-¡] - (6-morphol-4-ylmethyl-1 Hin dol-2-ll) -methanone as a yellow solid (74 mg, 75%).
1H-RMN (DMSO-Da) 8: 12.48 (1.0H, brs), 11.64 (1.0H, brs), 8.30 (1.0H, s), 7.64-7.60 (3.0H, m), 7.42-7.41 (2.0H, m), 7.29 (1.0H, dd, J = 8.5, 2.2 Hz), 7.06 (1.0H, dd, J = 8.3, 1.0 Hz), 6.99 (2.0H, brs), 3.58 (4.0H, t, J = 4.4 Hz), 3.55 (2.0H, s), 2.53 (3.0H, s), 2.39-2.37 (4.0H, brm) ESI (LC-MS modo positivo) m/z 456 [(M+H)+]1H-NMR (DMSO-Da) 8: 12.48 (1.0H, brs), 11.64 (1.0H, brs), 8.30 (1.0H, s), 7.64-7.60 (3.0H, m), 7.42-7.41 (2.0H , m), 7.29 (1.0H, dd, J = 8.5, 2.2 Hz), 7.06 (1.0H, dd, J = 8.3, 1.0 Hz), 6.99 (2.0H, brs), 3.58 (4.0H, t, J = 4.4 Hz), 3.55 (2.0H, s), 2.53 (3.0H, s), 2.39-2.37 (4.0H, brm) ESI (LC-MS positive mode) m / z 456 [(M + H) +]
Los compuestos de los Ejemplos 133 a 143 enumerados en la Tabla 5, se sintetizaron mediante el mismo método 5 como en el Ejemplo 132.The compounds of Examples 133 to 143 listed in Table 5, were synthesized by the same method 5 as in Example 132.
Tabla 5Table 5
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 133 133
- 9Hr- [5-amino-1-(2-metil-1H- bencimidazol- 5-il)- 1Hpirazol- 4-il]-[4-(2- morfolin-4-il-etilamino)- 1 H-indol-2-il]-metanona 485 1H-RMN (CD3OD) 8: 8.32 (1.0H, s), 7.73- 7.61 (2.0H, s), 7.58 (1.0H, d, J = 1.0 Hz), 7.38 (1H, dd, J = 8.8, 2.0 Hz), 7.11 (1H, t, J = 7.8 Hz), 6.79 (1H, d, J = 8.3 Hz), 6.21 (1H, d, J = 7.3 Hz), 3.77-3.72 (4H, m), 3.45 (2H, q. J = 6.0 Hz), 2.76 (2H, t. J = 6.0 Hz), 2.61 (3H, s), 2.55-2.63 (4H, m). 9Hr- [5-amino-1- (2-methyl-1H- benzimidazol-5-yl) -1Hpirazol-4-yl] - [4- (2- morpholin-4-yl-ethylamino) - 1 H-indole- 2-yl] -methanone 485 1H-NMR (CD3OD) 8: 8.32 (1.0H, s), 7.73- 7.61 (2.0H, s), 7.58 (1.0H, d, J = 1.0 Hz), 7.38 (1H, dd, J = 8.8, 2.0 Hz), 7.11 (1H, t, J = 7.8 Hz), 6.79 (1H, d, J = 8.3 Hz), 6.21 (1H, d, J = 7.3 Hz), 3.77-3.72 ( 4H, m), 3.45 (2H, q. J = 6.0 Hz), 2.76 (2H, t. J = 6.0 Hz), 2.61 (3H, s), 2.55-2.63 (4H, m).
- 134 134
- n [5-amino-1-(2-metil-1H- bencimidazol-5-il)- 1Hpirazol- 4-il]-[5-(4- metilpiperazina- 1- carbonil)-1 H-indol- 2-il]- metanona 483 1H-RMN (DMSO-D6) 8: 12.47 (1.0H, s), 11.91 (1.0H, s), 8.31 (1.0H, d, J = 4.4 Hz), 7.75 (1.0H, s), 7.66 (1.0H, m), 7.57 (1.0H, m), 7.52 (2.0H, m), 7.29 (2.0H, m), 7.10-7.00 (2.0H, m), 3.56-3.51 (4.0H, m), 2.53 (3.0H, s), 2.40-225 (4.0H, m), 2.21 (3.0H, s). n [5-amino-1- (2-methyl-1H- benzimidazol-5-yl) -1Hpyrazol- 4-yl] - [5- (4- methylpiperazine- 1- carbonyl) -1 H-indole-2-yl ] - methanone 483 1 H-NMR (DMSO-D6) 8: 12.47 (1.0H, s), 11.91 (1.0H, s), 8.31 (1.0H, d, J = 4.4 Hz), 7.75 (1.0H, s) , 7.66 (1.0H, m), 7.57 (1.0H, m), 7.52 (2.0H, m), 7.29 (2.0H, m), 7.10-7.00 (2.0H, m), 3.56-3.51 (4.0H, m), 2.53 (3.0H, s), 2.40-225 (4.0H, m), 2.21 (3.0H, s).
- 135 135
- [5-amino-1-(2-metil-1H- bencimidazol-5-il)- 1Hpirazol- 4-il]-[6-(2- morfolin-4-il-etilamino)- 1 H-indol-2-il]-metanona 485 1H-RMN (DMSO-D6) 8: 12.45 (1.0H, br s), 11.50 (1.0H, br s), 8.27 (1.0H, s), 7.60-7.55 (3.0H, m), 7.40 (1.0H, br s), 7.32-7.28 (1.0H, m), 5.93 (3.0H, br s), 6.75 (1.0H, dd, J = 8.8, 2.4 Hz), 4.11 (2.0H, t, J = 5.9 Hz), 3.60 (4.0H, t, J = 4.6 Hz), 3.34-3.28 (4.0H, m), 2.73 (2.0H, t, J = 5.9 Hz), 2.53 (3.0H, s). [5-amino-1- (2-methyl-1H- benzimidazol-5-yl) -1Hpirazol-4-yl] - [6- (2- morpholin-4-yl-ethylamino) - 1 H-indole-2- il] -methanone 485 1H-NMR (DMSO-D6) 8: 12.45 (1.0H, br s), 11.50 (1.0H, br s), 8.27 (1.0H, s), 7.60-7.55 (3.0H, m) , 7.40 (1.0H, br s), 7.32-7.28 (1.0H, m), 5.93 (3.0H, br s), 6.75 (1.0H, dd, J = 8.8, 2.4 Hz), 4.11 (2.0H, t , J = 5.9 Hz), 3.60 (4.0H, t, J = 4.6 Hz), 3.34-3.28 (4.0H, m), 2.73 (2.0H, t, J = 5.9 Hz), 2.53 (3.0H, s) .
- 136 136
- -O^TKh--' * ^xxy [5-amino-1-(2-metil-1H- bencimidazol- 1-il)- 1Hpirazol- 4-il]-[5- (piperazina- 1-carbonil)- 1 H-indol-2- il]-metanona 469 1H-RMN (CD3OD) 8: 8.28 (1.0H, s), 7.88 (1.0H, s), 7.68-7.64 (2.0H, m), 7.58 (1.0H, d, J = 8.3 Hz), 7.46 (1.0H, m), 7.40-7.35 (2.0H, m), 3.75 (4.0H, m), 3.01 (4.0H, m), 2.61 (3.0H, s). -O ^ TKh-- '* ^ xxy [5-amino-1- (2-methyl-1H- benzimidazol- 1-yl) - 1Hpyrazol- 4-yl] - [5- (piperazine-1-carbonyl) - 1 H-indole-2-yl] -methanone 469 1H-NMR (CD3OD) 8: 8.28 (1.0H, s), 7.88 (1.0H, s), 7.68-7.64 (2.0H, m), 7.58 (1.0H, d, J = 8.3 Hz), 7.46 (1.0H, m), 7.40-7.35 (2.0H, m), 3.75 (4.0H, m), 3.01 (4.0H, m), 2.61 (3.0H, s).
- 137 137
- [5-amino-1-(2-metil-1H- bencimidazol-5-il)- 1 Hpirazol- 4-il]-[4-(2- metoxietilamino)- 1 H-indol- 2-il]-metanona 430 1H-RMN (CD3OD) 6: 8.33 (1H, s), 7.66-7.59 (3H, m), 7.37 (1H, dd, J = 8.8, 2.0 Hz), 7.10 (1H, t, J = 7.8 Hz), 6.78 (1H, d, J = 8.3 Hz), 6.21 (1H, d, J = 7.3 Hz), 3.70 (2H, t, J = 5.8 Hz), 3.46 (2H, t, J = 5.8 Hz), 2.60 (3.0H, s) [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 Hpirazol-4-yl] - [4- (2- methoxyethylamino) -1 H-indol-2-yl] -methanone 430 1H-NMR (CD3OD) 6: 8.33 (1H, s), 7.66-7.59 (3H, m), 7.37 (1H, dd, J = 8.8, 2.0 Hz), 7.10 (1H, t, J = 7.8 Hz), 6.78 (1H, d, J = 8.3 Hz), 6.21 (1H, d, J = 7.3 Hz), 3.70 (2H, t, J = 5.8 Hz), 3.46 (2H, t, J = 5.8 Hz), 2.60 ( 3.0H, s)
- 138 138
- he -y*1 ^ [5-amino-1-(2-metil-1H- bencimidazol- 5-il)- 1 Hpirazol- 4-il]-[4-(2- hidroxi-1-hidroximetil - etilamino)-1 H-indol-2-il]- metanona 446 1H-RMN (CD3OD) 8: 8.35 (1H, s), 7.72-7.61 (3H, m), 7.37 (1H, dd, J = 8.8, 2.0 Hz), 7.10 (1H, t, J = 8.1 Hz), 6.78 (1H, d, J = 8.3 Hz, 6.29 (1H, d, J =7.8 Hz), 3.85-3.71 (5H, m), 2.61 (3H, s). he -y * 1 ^ [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 Hpirazol-4-yl] - [4- (2- hydroxy-1-hydroxymethyl-ethylamino) - 1 H-indole-2-yl] - methanone 446 1H-NMR (CD3OD) 8: 8.35 (1H, s), 7.72-7.61 (3H, m), 7.37 (1H, dd, J = 8.8, 2.0 Hz), 7.10 (1H, t, J = 8.1 Hz), 6.78 (1H, d, J = 8.3 Hz, 6.29 (1H, d, J = 7.8 Hz), 3.85-3.71 (5H, m), 2.61 (3H, s) .
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 139 139
- O [5-amino-1-(2-metil-1H- bencimidazol-5-il)- 1 Hpirazol-4-il]-[4-(2-piridin- 4-il-etilamino)-1 H-indol-2- ¡l]-metanona 477 1H-RMN (CD30D) 8: 8.43 (2H, dd, J = 4.4, 1.5 Hz), 8.30 (1H, s), 7.74-7.61 (2H,s), 7.57 (1H, s), 7.40-7.35 (3H, m), 7.13 (1H, t, J = 8.1 Hz), 6.79 (1H, d, J = 8.3 Hz), 6.26 (1H, d, J = 7.8 Hz), 3.61 (2H, t, J = 7.1 Hz), 3.09 (2H, t, J = 7.1 Hz), 2.62 (3H, s). O [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 Hpirazol-4-yl] - [4- (2-pyridin-4-yl-ethylamino) -1 H-indole- 2- 1] -methanone 477 1H-NMR (CD30D) 8: 8.43 (2H, dd, J = 4.4, 1.5 Hz), 8.30 (1H, s), 7.74-7.61 (2H, s), 7.57 (1H, s), 7.40-7.35 (3H, m), 7.13 (1H, t, J = 8.1 Hz), 6.79 (1H, d, J = 8.3 Hz), 6.26 (1H, d, J = 7.8 Hz), 3.61 ( 2H, t, J = 7.1 Hz), 3.09 (2H, t, J = 7.1 Hz), 2.62 (3H, s).
- 140 140
- [5-am¡no-1-(2-metil-1H- bencimidazol- 5-¡l)- IHpirazol- 4-il]-[6-(2- metoxietilamino)-1 H-indol- 2-¡l]-metanona 430 1H-RMN (CD30D) 8: 8.23 (1 .OH, s), 7.67 (2.OH, br s), 7.46-7.44 (1 OH, m), 7.38 (1 .OH dd. J = 8.8, 2.0 Hz), 7.27 (1 .OH, s), 6.63-6.60 (2.0H, m), 3.65 (2.OH, t, J = 5.4 Hz), 3.41 (3.0H, s), 3.34 (2.OH, t, J = 5.4 Hz), 2.62 (3.OH, s). [5-am-1-1 (2-methyl-1 H- benzimidazol-5-l) - I-pyrazol-4-yl] - [6- (2- methoxyethylamino) -1 H-indole-2-l] -methanone 430 1H-NMR (CD30D) 8: 8.23 (1 .OH, s), 7.67 (2.OH, br s), 7.46-7.44 (1 OH, m), 7.38 (1 .OH dd. J = 8.8 , 2.0 Hz), 7.27 (1 .OH, s), 6.63-6.60 (2.0H, m), 3.65 (2.OH, t, J = 5.4 Hz), 3.41 (3.0H, s), 3.34 (2. OH, t, J = 5.4 Hz), 2.62 (3.OH, s).
- 141 141
- O [5-amino-1-(2-met¡l-1H- bencimidazol- 5-il)- 1 Hpirazol-4-il]-(6-morfoli n- 4-M-1 H-indol-2-il)- metanona 442 1H-RMN (DMSO-D6) 8: 12.48 (1 .OH, br s), 11.39 (1 OH, br s), 8.27 (1 OH, s), 7.61 (2.OH, br s), 7.54 (1 .OH, d, J = 8.8 Hz), 7.35 (1 OH, d, J = 2.0 Hz), 7.29 (1 .OH, dd, J = 8.3, 2.0 Hz), 6.93- 6.91 (3.OH, m), 6.84 (1 .OH, br s), 3.78 (4.OH, t, J = 4.8 Hz), 3.12 (4.0H, t, J = 4.8 Hz), 2.53 (3.OH, s). O [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1 Hpirazol-4-yl] - (6-morpholi n- 4-M-1 H-indole-2-yl ) - methanone 442 1H-NMR (DMSO-D6) 8: 12.48 (1 .OH, br s), 11.39 (1 OH, br s), 8.27 (1 OH, s), 7.61 (2.OH, br s) , 7.54 (1 .OH, d, J = 8.8 Hz), 7.35 (1 OH, d, J = 2.0 Hz), 7.29 (1 .OH, dd, J = 8.3, 2.0 Hz), 6.93-6.91 (3. OH, m), 6.84 (1 .OH, br s), 3.78 (4.OH, t, J = 4.8 Hz), 3.12 (4.0H, t, J = 4.8 Hz), 2.53 (3.OH, s) .
- 142 142
- xr [5-amino-1-(2-met¡l-1H- bencimidazol- 5-il)- IHpirazol- 4-M]-(4-morfolin- 4-M-1 H-indol-2-il)- metanona 442 1H-RMN (CD30D) 8: 8.23 (1H, s), 7.67 (2H, s), 7.38 (1H, dd, J = 8.8, 2.0 Hz) 7.29 (1H, s), 7.23-7.14 (2H, m), 6.63-6.60 (1H, m), 3.99-3.94 (4H, m), 3.27-3.22 (4H, m), 2.61 (3H, s). xr [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -I-pyrazol-4-M] - (4-morpholin-4-M-1 H-indole-2-yl) - methanone 442 1H-NMR (CD30D) 8: 8.23 (1H, s), 7.67 (2H, s), 7.38 (1H, dd, J = 8.8, 2.0 Hz) 7.29 (1H, s), 7.23-7.14 (2H, m), 6.63-6.60 (1H, m), 3.99-3.94 (4H, m), 3.27-3.22 (4H, m), 2.61 (3H, s).
- 143 143
- [5-ami no-1 -(2-metil-1 H- bendmidazol-5-il)- 1 Hpirazol-4-il]-(4-morfolin- 4-ilmetil-1 H-indol-2-il)- metanona 456 1H-RMN [CD30D) 8: 8.31 (1H, s), 7.75-7.62 (2H, m), 7.59 (1H, s), 7.45- 7.37 (2H, m), 7.25 (1H, t, J = 7.8 Hz), 7.10-7.06 (1H, m), 3.88 (2H, s), 3.75- 3.69 (4H, m), 2.62 (3H, s), 2.60-2.53 (4H, m). 2.55 (3.0H, s), 2.38 (4.0H, m) ESI (LC-MS modo positivo) m/z 456 [(M+H)+j [5-ami no-1 - (2-methyl-1 H- bendmidazol-5-yl) - 1 Hpirazol-4-yl] - (4-morpholin-4-ylmethyl-1 H-indole-2-yl) - methanone 456 1H-NMR [CD30D) 8: 8.31 (1H, s), 7.75-7.62 (2H, m), 7.59 (1H, s), 7.45-7.37 (2H, m), 7.25 (1H, t, J = 7.8 Hz), 7.10-7.06 (1H, m), 3.88 (2H, s), 3.75- 3.69 (4H, m), 2.62 (3H, s), 2.60-2.53 (4H, m). 2.55 (3.0H, s), 2.38 (4.0H, m) ESI (LC-MS positive mode) m / z 456 [(M + H) + j
[Ejemplo 144: Síntesis de la [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-p¡razol-4-il]-(5-morfolin-4-¡lmet¡l-1H-¡ndol- 2-il)-metanona][Example 144: Synthesis of [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-p¡razol-4-yl] - (5-morpholin-4-lmetl) -1H-¡ndol- 2-il) -methanone]
5 Se adicionó carbonato de cesio (1.29 g) a una solución en metanol (20 mi) de [5-amino-1-(2-metil-1H-bencimidazol- 5-¡l)-1H-pirazol-4-il]-(1-bencenosulfonil-5-morfolin -4-ilmetil-1H-indol-2-il)-metanona (110 mg), y se agitó a temperatura ambiente, durante 16 horas. A continuación, se adicionaron agua (5 mi) y agua de amoníaco (3 mi) a la mezcla de reacción y se agitó durante tres horas. La mezcla de reacción se concentró bajo presión reducida. Se adicionó agua al residuo resultante. Después de la extracción con acetato de etilo, el extracto se lavó con una 10 solución acuosa saturada de cloruro de sodio, y a continuación se secó sobre sulfato de sodio anhidro. El desecante se eliminó por filtración. El filtrado se concentró bajo presión reducida. El residuo resultante se purificó por cromatografía de columna de sílica gel (metanol/diclorometano = 0/100 a 20/100) para dar la [5-amino-1-(2-metil-1H- bencimidazol-5-il)-1 H-pirazol-4-il]-(5-morfol¡n-4-ilmetil-1 H-in dol-2-¡l)-metanona (33 mg).5 Cesium carbonate (1.29 g) was added to a methanol solution (20 ml) of [5-amino-1- (2-methyl-1H-benzimidazol-5-l) -1H-pyrazole-4-yl] - (1-Benzenesulfonyl-5-morpholin-4-ylmethyl-1H-indole-2-yl) -methanone (110 mg), and stirred at room temperature for 16 hours. Then, water (5 ml) and ammonia water (3 ml) were added to the reaction mixture and stirred for three hours. The reaction mixture was concentrated under reduced pressure. Water was added to the resulting residue. After extraction with ethyl acetate, the extract was washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol / dichloromethane = 0/100 to 20/100) to give [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - (5-morphol-4-ylmethyl-1 H-in dol-2-l) -methanone (33 mg).
1H-RMN (DMSO-Dg) 8: 12.47 (1 .OH, s), 11.67 (1.0H, s), 8.30 (1 .OH, s), 7.60 (3.0H, m), 7.44 (2.0H, m), 7.30 (1 OH, dd, J = 8.4, 2.1 Hz), 7.23 (1 .OH, dd, J = 8.4, 1.5 Hz), 7.01 (2.0H, m), 3.58 (4.0H, t, J = 4.4 Hz), 3.54 (2.0H, s), 2.55 (3.0H, s), 2.38 (4.OH, m)1 H-NMR (DMSO-Dg) 8: 12.47 (1 .OH, s), 11.67 (1.0H, s), 8.30 (1 .OH, s), 7.60 (3.0H, m), 7.44 (2.0H, m ), 7.30 (1 OH, dd, J = 8.4, 2.1 Hz), 7.23 (1 .OH, dd, J = 8.4, 1.5 Hz), 7.01 (2.0H, m), 3.58 (4.0H, t, J = 4.4 Hz), 3.54 (2.0H, s), 2.55 (3.0H, s), 2.38 (4.OH, m)
ESI (LC-MS modo positivo) m/z 456 [(M+H)+]ESI (LC-MS positive mode) m / z 456 [(M + H) +]
5 Los compuestos de los Ejemplos 145 a 164 enumerados en la Tabla 6, se sintetizaron mediante el mismo método como en el Ejemplo 144.The compounds of Examples 145 to 164 listed in Table 6, were synthesized by the same method as in Example 144.
Tabla 6Table 6
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 145 145
- [5-amino-1-(2-met¡l-1 H- bencimidazol- 5-¡l)-1H- pirazol- 4-il] -[2-(morfolina- 4- carbonil)-1 H-indol-2-ilj- metanona 470 1H-RMN (DMSO-D6) 8: 12.47 (1 .OH, s), 11.92 (1 .OH, s), 8.31 (1 .OH, s), 7.79 (1 .OH, s), 7.61 (2.0H, m), 7.53 (2.OH, m), 7.32-7.29 (1 .OH, m), 7.32 (1 .OH, dd, J = 8.8, 1.6 Hz), 7.10-6.95 (2.OH, m), 3.62-3.51 (8.0H, m), 2.54 (3.OH, s). [5-amino-1- (2-methyl-1 H- benzimidazol-5-l) -1 H- pyrazol-4-yl] - [2- (morpholine-4-carbonyl) -1 H-indole- 2-yl-methanone 470 1H-NMR (DMSO-D6) 8: 12.47 (1 .OH, s), 11.92 (1 .OH, s), 8.31 (1 .OH, s), 7.79 (1 .OH, s ), 7.61 (2.0H, m), 7.53 (2.OH, m), 7.32-7.29 (1 .OH, m), 7.32 (1 .OH, dd, J = 8.8, 1.6 Hz), 7.10-6.95 ( 2.OH, m), 3.62-3.51 (8.0H, m), 2.54 (3.OH, s).
- 146 146
- C [5-am¡no-1-(2-isopropil-1 H- bencimidazolo-il)-1 H- plrazol- 4-il] -(1H-indol-2- ¡l)-metanona 385 1H-RMN (CD30D) 8: 8.28 (1H, s), 7.73-7.67 (3H, m), 7.50-7.47 (1H, m), 7.40-7.37 (2H, m), 7.29-7.24 (1H, m), 7.12-7.07 (1H, m), 3.30-3.247 (2H, m), 1.46 (6H, d, J = 7.6 Hz). C [5-amine-1- (2-isopropyl-1 H- benzimidazolo-yl) -1 H- plrazol-4-yl] - (1H-indole-2- 1) -methanone 385 1 H-NMR ( CD30D) 8: 8.28 (1H, s), 7.73-7.67 (3H, m), 7.50-7.47 (1H, m), 7.40-7.37 (2H, m), 7.29-7.24 (1H, m), 7.12-7.07 (1H, m), 3.30-3.247 (2H, m), 1.46 (6H, d, J = 7.6 Hz).
- 147 147
- [5-amlno-1-(2-propil-1 H- benclmldazol- 5-il)-1H- plrazol- 4-il] -(1H-indol-2- il)-metanona 385 1H-RMN (DMSO-D6) 8: 12.46 (1H, s), 11.70 (1H, s), 8.31 (1H, s), 7.71- 7.66 (2H, m), 7.59-7.57 (1H, m), 7.50- 7.45 (2H, m), 7.32-1.23 (2H, m), 7.10- 6.98 (3H, m), 2.83 (2H, t, J = T.4 Hz], 7.85-1.79 (2H, m), 0.96 (3H, t, J = 7.3 Hz). [5-amlno-1- (2-propyl-1 H- benclmldazol- 5-yl) -1H- plrazol-4-yl] - (1H-indole-2-yl) -methanone 385 1 H-NMR (DMSO-D6 ) 8: 12.46 (1H, s), 11.70 (1H, s), 8.31 (1H, s), 7.71- 7.66 (2H, m), 7.59-7.57 (1H, m), 7.50- 7.45 (2H, m) , 7.32-1.23 (2H, m), 7.10-6.98 (3H, m), 2.83 (2H, t, J = T.4 Hz], 7.85-1.79 (2H, m), 0.96 (3H, t, J = 7.3 Hz).
- 148 148
- H n [5-amino-1-(1H- bencimidazol- 5-¡l) -1H- pirazol-4-il]-(1 H-indol- 2-¡l)- metanona 343 1H-RMN (CD30D) 8: 8.32 (1H, s), 8.29 (1H, s), 7.83-7.80 (2H, m), 7.72 (1H, d, d=8.1 Hz), 7.50-7.46 (2H, m), 7.38 (1H, s), 7.27 (1H, t, J = 7.2 Hz), 7.09 (1H, t, J = 7.2 Hz). H n [5-amino-1- (1 H- benzimidazol-5-1) -1 H- pyrazol-4-yl] - (1 H-indol-2-1) - methanone 343 1 H-NMR (CD30D) 8 : 8.32 (1H, s), 8.29 (1H, s), 7.83-7.80 (2H, m), 7.72 (1H, d, d = 8.1 Hz), 7.50-7.46 (2H, m), 7.38 (1H, s ), 7.27 (1H, t, J = 7.2 Hz), 7.09 (1H, t, J = 7.2 Hz).
- 149 149
- [5-am¡no-1-(2-trifluoromet¡l- 1 H-bencimidazol-5-il)- 1 Hpirazol- 4-il] -(1 H-indol- 2-¡l)-metanona 411 1H-RMN (DMSO-D6) 8: 12.58 (1H, s), 11.71 (1H, s), 8.35 (1H, s), 7.89- 7.81 (2H, m), 7.70 (1H, d, J = 7.4 Hz), 7.50-7-46 (3H, m), 7.27-7.23 (1H, m), 7.10-7.06 (3H, m). [5-amine-1- (2-trifluoromethyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4-yl] - (1 H-indole-2-l) -methanone 411 1H- NMR (DMSO-D6) 8: 12.58 (1H, s), 11.71 (1H, s), 8.35 (1H, s), 7.89-7.81 (2H, m), 7.70 (1H, d, J = 7.4 Hz), 7.50-7-46 (3H, m), 7.27-7.23 (1H, m), 7.10-7.06 (3H, m).
- 150 150
- [5-am¡no-1-(2-etil-1H- bencimidazol-5-il)-1 H- pirazol- 4-il] -(1H-indol-2- il)-metanona 371 1H-RMN (DMSO-D6) 8: 12.40 (1H, s), 11.68 (1H, s), 8.26 (1H, s), 7.66- 7.64 (1H, m), 7.61-7.52 (2H, m), 7.45- 7.40 (2H, m), 7.26-7.18 (2H, m), 7.05- 7.01 (1H, m), 6.90 (1.1H, s), 2.83 (2H, d, J = 7.6 Hz), 1.29 (3H, t, J = 7.5 Hz). [5-amine-1- (2-ethyl-1 H- benzimidazol-5-yl) -1 H- pyrazol-4-yl] - (1 H -indol-2- yl) -methanone 371 1 H-NMR (DMSO -D6) 8: 12.40 (1H, s), 11.68 (1H, s), 8.26 (1H, s), 7.66- 7.64 (1H, m), 7.61-7.52 (2H, m), 7.45-7.40 (2H, m), 7.26-7.18 (2H, m), 7.05-7.01 (1H, m), 6.90 (1.1H, s), 2.83 (2H, d, J = 7.6 Hz), 1.29 (3H, t, J = 7.5 Hz)
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 151 151
- o^j^ano [5-amino-1-(2-bencil-1 H- bencimidazol-5-il)-1 H-pirazol- 4-il] -(1H-indol-2-il)metanona 433 1H-RMN (DMSO-D6) 8: 12.60 (1H, s), 11.70 (1H, s), 8.31 (1H. s), 7.69 (1H, d, J = 8.2 Hz), 7.67-7.59 (2H, m), 7.49-7.45 (2H, m), 7.37-7.23 (7H, m), 7.10-7.06 (1H, m), 7.03-6.97 (2H, m), 4.22 (2H, s). or ^ j ^ ano [5-amino-1- (2-benzyl-1 H- benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (1H-indole-2-yl) methanone 433 1H- NMR (DMSO-D6) 8: 12.60 (1H, s), 11.70 (1H, s), 8.31 (1H. S), 7.69 (1H, d, J = 8.2 Hz), 7.67-7.59 (2H, m), 7.49-7.45 (2H, m), 7.37-7.23 (7H, m), 7.10-7.06 (1H, m), 7.03-6.97 (2H, m), 4.22 (2H, s).
- 152 152
- 1-(4-{2-[5-amino-1-(2-metil- 1H- bencimidazol-5-il)-1Hpirazol- 4- carbon¡l]-1 H-¡ndol- 5-ilmetll}- piperazin-1-il)-etanona 497 1H-RMN (CD30D) 8: 8.27 (1.0H, s), 7.66 (3.OH, m), 7.46 (1.0H, d. J = 8.3 Hz), 7.38 (1.0H, dd, J= 8.8, 2.0 Hz), 7.35 (1.0H, s), 7.30 (1.0H, dd, J = 8.5, 1.7 Hz), 3.64 (2.0H, s), 3.56 (4.2H, dt, J = 21.6, 4.9 Hz), 2.61 (3.OH, s), 2.49 (4.0H, td, J = 10.5, 5.5 Hz), 2.07 (3.OH, s). 1- (4- {2- [5-amino-1- (2-methyl- 1H- benzimidazol-5-yl) -1Hyrazol- 4- carbonl] -1 H-¡ndol- 5-ylmetll} - piperazin -1-yl) -ethanone 497 1H-NMR (CD30D) 8: 8.27 (1.0H, s), 7.66 (3.OH, m), 7.46 (1.0H, d. J = 8.3 Hz), 7.38 (1.0H , dd, J = 8.8, 2.0 Hz), 7.35 (1.0H, s), 7.30 (1.0H, dd, J = 8.5, 1.7 Hz), 3.64 (2.0H, s), 3.56 (4.2H, dt, J = 21.6, 4.9 Hz), 2.61 (3.OH, s), 2.49 (4.0H, td, J = 10.5, 5.5 Hz), 2.07 (3.OH, s).
- 153 153
- [5-amlno-1-(2-metil-1H- bencimidazol- 5-il)-1 H-p¡razol- 4-II] -[5-(4- metanosulfonllplperazln-1- ilmetil)-1 H-indol- 2-¡l]-metanona 533 1H-RMN (CD30D) 8: 8.27 (1:0H, s), 7.67 (3.0H, m), 7.4.6 (1.0H, d, J = 8.3 Hz), 7.38 (1.0H, dd, J = 8.3, 2.0 Hz). 7.35 (1.0H, s). 7.30 (1.0H, dd, J = 8.3, 1.5 Hz), 3.67 (2.0H, s), 3.23 (4.OH, s), 2.83 (3.0H, s), 2.65-2.55 (4.OH, m), 2.61 (3.0H, s)- [5-amlno-1- (2-methyl-1H- benzimidazol-5-yl) -1 Hp¡razol- 4-II] - [5- (4- methanesulfonllplperazln-1- ylmethyl) -1 H-indole-2 -¡L] -methanone 533 1H-NMR (CD30D) 8: 8.27 (1: 0H, s), 7.67 (3.0H, m), 7.4.6 (1.0H, d, J = 8.3 Hz), 7.38 (1.0 H, dd, J = 8.3, 2.0 Hz). 7.35 (1.0H, s). 7.30 (1.0H, dd, J = 8.3, 1.5 Hz), 3.67 (2.0H, s), 3.23 (4.OH, s), 2.83 (3.0H, s), 2.65-2.55 (4.OH, m) , 2.61 (3.0H, s) -
- 154 154
- TXO^ys; [5-amino-1-(2-met¡l-1H- bencimidazol-5-¡l)-1 H-pirazol- 4-il] -(5-piperazin-1 -ilmetil- 1H- indol-2 -N)-metanona 455 1H-RMN (CD30D) 8: 8.28 (1.0H, s), 7.70-7.62 (3.0H, m), 7.47 (1.1H, d, J = 8.8 Hz), 7.39 (1.0H, dd, J = 8.3, 2.0 Hz), 7.36 (1.0H, d, J = 1.0 Hz), 7.30 (1.0H, dd, J = 8.8, 1.5 Hz), 3.67-3.60 (2.OH, m), 2.95-2.85 (4.OH, m), 2.62 (3.0H, s), 2.60- 2.50 (2.OH, s). TXO ^ ys; [5-amino-1- (2-methyl-1H-benzimidazol-5-l) -1 H -pyrazol-4-yl] - (5-piperazin-1-methylmethyl-1H- indole-2-N ) -methanone 455 1H-NMR (CD30D) 8: 8.28 (1.0H, s), 7.70-7.62 (3.0H, m), 7.47 (1.1H, d, J = 8.8 Hz), 7.39 (1.0H, dd, J = 8.3, 2.0 Hz), 7.36 (1.0H, d, J = 1.0 Hz), 7.30 (1.0H, dd, J = 8.8, 1.5 Hz), 3.67-3.60 (2.OH, m), 2.95-2.85 (4.OH, m), 2.62 (3.0H, s), 2.60-2.50 (2.OH, s).
- 155 155
- r0XHi“ys 1-(4-{2-[5-amino-1-(2-metil-1H- bencimidazol-5-¡l)-1Hp¡razol- 4- carbonil]-1 H-indol- 6-ilmetil;’ - piperazin-1-¡l)-etanona 497 1H-RMN (DMSO-D6) 8: 12.49 (1 .OH, br s), 11.66 (1.0H, br s), 8.30 (1 OH, s), 7.66-1.60 (3.0H, m), 7.43-7.41 (2.0H, m), 7.29 (1 .OH, dd, J = 8.3, 2.0 Hz), 7.06 (1 .OH, dd, J = 8.3, 1.0 Hz), 5.99 (2.OH, br s), 3.58 (2.0H, s), 3.45-3.41 (4.OH, m), 2.53 (3.0H, s), 2.39 (2.OH, t, J = 4.6 Hz), 233 (2.OH, t, J = 4.9 Hz), 1.98 (3.OH, s). r0XHi "ys 1- (4- {2- [5-amino-1- (2-methyl-1H- benzimidazol-5-α) -1Hp¡razol- 4- carbonyl] -1 H-indole-6-ylmethyl ; '- piperazin-1-1) -ethanone 497 1 H-NMR (DMSO-D6) 8: 12.49 (1 .OH, br s), 11.66 (1.0H, br s), 8.30 (1 OH, s), 7.66-1.60 (3.0H, m), 7.43-7.41 (2.0H, m), 7.29 (1 .OH, dd, J = 8.3, 2.0 Hz), 7.06 (1 .OH, dd, J = 8.3, 1.0 Hz ), 5.99 (2.OH, br s), 3.58 (2.0H, s), 3.45-3.41 (4.OH, m), 2.53 (3.0H, s), 2.39 (2.OH, t, J = 4.6 Hz), 233 (2.OH, t, J = 4.9 Hz), 1.98 (3.OH, s).
- 156 156
- [5-amino-1-(2-met¡l-1H- bencimidazol- 5-il)-1 H-pirazol- 4-il] -[6-(4-metil-piperaz¡n-1- ilmetil) -1 H-¡ndol-2-¡l]-metanona 469 1H-RMN (DMSO-D6) 8: 12.47 (1 .OH, br s), 11.63 (1 OH, br s), 8.30 (1 .OH, s), 7.65-7.56 (3.0H, m), 7.42-7.40 (2.0H, m), 7.30- 7.28 (1 .OH, m), 7.04-6.97 (3.0H, m), 3.53 (2.OH, s), 3.36-3.30 (4.OH, m), 2.53 (3.0H, s), 2.46- 2.33 (4.OH, m), 2.15 (3.0H, s). [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6- (4-methyl-piperazine-1-ylmethyl) - 1 H-¡-ol-2-¡1] -methanone 469 1 H-NMR (DMSO-D6) 8: 12.47 (1 .OH, br s), 11.63 (1 OH, br s), 8.30 (1 .OH, s ), 7.65-7.56 (3.0H, m), 7.42-7.40 (2.0H, m), 7.30- 7.28 (1 .OH, m), 7.04-6.97 (3.0H, m), 3.53 (2.OH, s ), 3.36-3.30 (4.OH, m), 2.53 (3.0H, s), 2.46-2.33 (4.OH, m), 2.15 (3.0H, s).
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 157 157
- 0jítH£rp: [5-amino-1-(2-metil-1 H- bencimidazol-5-il)-1 H- pirazol- 4-il] -[5-(4-metil- piperazin-1-ilmetil) -1H- indol-2-il]-metanona 469 1H-RMN (CD3OD) 8: 8.27 (1.0H, s), 7.66 (3.0H, m), 7.45 (1.0H, d, J = 8.3 Hz), 7.40-7.33 (2.0H, m), 7.31-7.25 (1.0H, m), 3.64 (2.0H, s), 2.70-2.40 (8H, m), 2.61 (3.0H, s), 2.28 (3.0H, s). 0jítH £ rp: [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 H- pyrazol- 4-yl] - [5- (4-methyl-piperazin-1-ylmethyl) -1H- indole-2-yl] -methanone 469 1H-NMR (CD3OD) 8: 8.27 (1.0H, s), 7.66 (3.0H, m), 7.45 (1.0H, d, J = 8.3 Hz), 7.40 -7.33 (2.0H, m), 7.31-7.25 (1.0H, m), 3.64 (2.0H, s), 2.70-2.40 (8H, m), 2.61 (3.0H, s), 2.28 (3.0H, s ).
- 158 158
- [5-amino-1-(2-metil-1 H- bencimidazol-5-il)-1 H- pirazol-4-il] -(5-pirrolidin- 1-ilmetil-1 H-indol -2-il)- metanona 440 1H-RMN (CD30D) 8: 8.27 (1.0H, s), 7.66 (3.0H, m), 7.46 (1.0H, d, J = 8.3 Hz), 7.38 (1.0H, dd, J = 8.3, 2.0 Hz), 7.35 (1.0H, s), 7.30 (1.0H, dd, J = 8.5, 1.7 Hz), 3.75 (2.0H, s), 2.65-2.55(4.0H, m), 2.61(3.0H, s), 1.82 (4.0H, s). [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 H- pyrazol-4-yl] - (5-pyrrolidin-1-ylmethyl-1 H-indole -2-yl) - methanone 440 1H-NMR (CD30D) 8: 8.27 (1.0H, s), 7.66 (3.0H, m), 7.46 (1.0H, d, J = 8.3 Hz), 7.38 (1.0H, dd, J = 8.3 , 2.0 Hz), 7.35 (1.0H, s), 7.30 (1.0H, dd, J = 8.5, 1.7 Hz), 3.75 (2.0H, s), 2.65-2.55 (4.0H, m), 2.61 (3.0H , s), 1.82 (4.0H, s).
- 159 159
- H ^ ' <*or [5-amino-1-(2-metil-1 H- bencimidazol- 5-il)-1H- pirazol- 4-il] -(4-fluoro- 1 H-indol-2-il)-metanona 375 1H-RMN (DMSO-D5) 8: 12.46 (1H, s), 12.04 (1H, s), 8.36 (1H, s), 7.68-7-55 (2H, m), 7.45 (1H, s), 7.34-7.20 (3H, m), 7.09-6.97 (2H, m), 6.88-6.84 (1H, m), 2.53 (3H, s). H ^ '<* or [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1H- pyrazol- 4-yl] - (4-fluoro- 1 H-indole-2-yl ) -methanone 375 1 H-NMR (DMSO-D5) 8: 12.46 (1H, s), 12.04 (1H, s), 8.36 (1H, s), 7.68-7-55 (2H, m), 7.45 (1H, s), 7.34-7.20 (3H, m), 7.09-6.97 (2H, m), 6.88-6.84 (1H, m), 2.53 (3H, s).
- 160 160
- H [5-amino-1-(2-metil-1 H- bencimidazol-5-il)-1 H- pirazol- 4-il] -(5-fluoro- 1 H-indol-2-il)-metanona 375 1H-RMN (DMSO-D8) 8: 12.48 (1H, s), 11.81 (1H, s), 8.29 (1H, s), 7.69-7.53 (2H, ml), 7.50-7.47 (1H, m), 7.44-7.41 (2H, m), 7.29 (1H, dd, J = 8-4, 2.0 Hz), 7.15-7.10 (1H, m), 7.07-6.97 (2H, s), 2.53 (3H, s). H [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 H- pyrazol-4-yl] - (5-fluoro-1 H-indole-2-yl) -methanone 375 1H-NMR (DMSO-D8) 8: 12.48 (1H, s), 11.81 (1H, s), 8.29 (1H, s), 7.69-7.53 (2H, ml), 7.50-7.47 (1H, m), 7.44 -7.41 (2H, m), 7.29 (1H, dd, J = 8-4, 2.0 Hz), 7.15-7.10 (1H, m), 7.07-6.97 (2H, s), 2.53 (3H, s).
- 161 161
- v'-o r [-amino-1-(2-metil-1H- bencimidazol-5-il)-1 H- pirazol- 4-il] -(6-fluoro- 1 H-indol-2-il)-metanona 375 1H-RMN (DMSO-D6) 8: 12.48 (1H, s), 11.78 (1H, s), 8.30 (1H, s), 7.73-7.70 (1H, m), 7.54-7.56 (2H, m), 7.49 (1H, s), 7.30-7-27 (1H, m), 7.20-7.17 (1H, m), 7.00-6.94 (3H, m), 2.53 (3H, s). v'-or [-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 H- pyrazol-4-yl] - (6-fluoro- 1 H-indole-2-yl) -methanone 375 1H-NMR (DMSO-D6) 8: 12.48 (1H, s), 11.78 (1H, s), 8.30 (1H, s), 7.73-7.70 (1H, m), 7.54-7.56 (2H, m), 7.49 (1H, s), 7.30-7-27 (1H, m), 7.20-7.17 (1H, m), 7.00-6.94 (3H, m), 2.53 (3H, s).
- 162 162
- cjH,- [5-amino-1-(2-metil-1 H- bencimidazol-5-il)-1 H- pirazol- 4-il) -(1H- pirrolo[2,3-b]piridin- 2-il)- metanona 358 1H-RMN (DMSO-D6) 8: 12.48 (1H, s), 12.23 (1H, s), 8.40 (1H, dd, J = 4.6,1.7 Hz), 8.27 (1H, s), 8.13 (1H, dd, J = 8.0, 1.6 Hz), 7.61 (2H, m), 7.41 (1H, s), 7.29 (1H, dd, J = 8.5, 2.1 Hz), 7.18-7.15 (1H, m), 7.04 (2H, s), 2.53 (3.6H, s). cjH, - [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 H- pyrazol-4-yl) - (1H- pyrrolo [2,3-b] pyridin-2- il) - methanone 358 1H-NMR (DMSO-D6) 8: 12.48 (1H, s), 12.23 (1H, s), 8.40 (1H, dd, J = 4.6.1.7 Hz), 8.27 (1H, s), 8.13 (1H, dd, J = 8.0, 1.6 Hz), 7.61 (2H, m), 7.41 (1H, s), 7.29 (1H, dd, J = 8.5, 2.1 Hz), 7.18-7.15 (1H, m) , 7.04 (2H, s), 2.53 (3.6H, s).
- 163 163
- °'x¡^£<ír [5-amino-1-(2-metil-1 H- bencimidazol- 5-il)-1H- pirazol- 4-il) -(5-fluoro-6- morfolin-4-ilmetil-1 H- indol-2-il)-metanona 474 1H-RMN (DMSO-D6) 8: 12.46 (1H, m), 11.74 (1H, s), 8.28 (1H, d, J = 5.1 Hz), 7.67-7.63 (1H, m), 7.58-T.56 (1H, m), 7.49 (1H, d, J = 6.3 Hz), 7.42-7.39 (2H, m), 7.31.7.27 (1H, m), 7.05-6.99 (2H, m), 3.62-3.55 (6H, m), 2.53 (3H, s), 2.47-2.39 (4H, m). ° 'x¡ ^ £ <ír [5-amino-1- (2-methyl-1 H- benzimidazol- 5-yl) -1H- pyrazol- 4-yl) - (5-fluoro-6- morpholin-4- ilmethyl-1 H- indole-2-yl) -methanone 474 1H-NMR (DMSO-D6) 8: 12.46 (1H, m), 11.74 (1H, s), 8.28 (1H, d, J = 5.1 Hz), 7.67-7.63 (1H, m), 7.58-T.56 (1H, m), 7.49 (1H, d, J = 6.3 Hz), 7.42-7.39 (2H, m), 7.31.7.27 (1H, m), 7.05-6.99 (2H, m), 3.62-3.55 (6H, m), 2.53 (3H, s), 2.47-2.39 (4H, m).
- 164 164
- ácido 2-[5-amino-1-(2- metil-1 H-bencimidazol- 5-il)-1 Hpirazol- 4- carbonill]-1 H-indol- 5- carboxílico 401 1H-RMN (DMSO-D6) 8: 12.57 (1.0H, s), 12.47 (1.0H, d, J = 5.4 Hz), 12.04 (1.0H, s), 8.40 (1.0H, s), 8.34 (1.0H, t, J = 4.6 Hz), 7.84 (1.0H, dd, J = 8.5, 1.7 Hz), 7.68-7.62 (2.0H, m), 7.57 (1.0H, d, J = 8.3 Hz), 7.53 (1.0H, d, J = 8.3 Hz), 7.29 (1.0H, m), 7.10-6.95 (2.0H, m), 2.54 (3.0H, s). 2- [5-amino-1- (2- methyl-1 H-benzimidazol-5-yl) -1 Hpyrazol- 4- carbonill] -1 H-indole-5-carboxylic acid 401 1H-NMR (DMSO-D6) 8: 12.57 (1.0H, s), 12.47 (1.0H, d, J = 5.4 Hz), 12.04 (1.0H, s), 8.40 (1.0H, s), 8.34 (1.0H, t, J = 4.6 Hz ), 7.84 (1.0H, dd, J = 8.5, 1.7 Hz), 7.68-7.62 (2.0H, m), 7.57 (1.0H, d, J = 8.3 Hz), 7.53 (1.0H, d, J = 8.3 Hz), 7.29 (1.0H, m), 7.10-6.95 (2.0H, m), 2.54 (3.0H, s).
Etapa 1: Síntesis de [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(1-bencenosulfonil-1H-indol-2-il)- metanona (1001)Stage 1: Synthesis of [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (1-benzenesulfonyl-1H-indole-2-yl) - methanone (1001)
Se adicionó (2-metil-1H-bencimidazol-5-il)-hidrazina diclorhidrato (830 mg) a una solución en etanol (15 mi) de 2-(1- bencenosulfonil-1H-indol-2-carbonil)-3-dimetilamino acrilonitrilo en bruto (1.17 g). La mezcla de reacción se calentó con agitación bajo reflujo, durante cuatro horas. Después de enfriar a temperatura ambiente, la mezcla se dejó en 5 reposo a temperatura ambiente. El sólido precipitado se recolectó por filtración, y se lavó con etanol para dar la [5- amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(1-bencenosulfonil-1H-indol-2-il)-metanona, obtenida como un sólido de color amarillo (1.5 g, con un rendimiento de dos etapas del 91%).(2-Methyl-1H-benzimidazol-5-yl) -hydrazine dihydrochloride (830 mg) was added to a solution in ethanol (15 ml) of 2- (1- benzenesulfonyl-1H-indole-2-carbonyl) -3- crude dimethylamino acrylonitrile (1.17 g). The reaction mixture was heated with stirring under reflux for four hours. After cooling to room temperature, the mixture was allowed to stand at room temperature. The precipitated solid was collected by filtration, and washed with ethanol to give [5- amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - (1-benzenesulfonyl -1H-indole-2-yl) -methanone, obtained as a yellow solid (1.5 g, with a two-stage yield of 91%).
1H-RMN (DMSO-De) 8: 8.15-8.13 (2H, m), 8.02 (1H, dd, J = 8.4, 0.8 Hz), 7.97 (1H, d, J = 2.0 Hz), 7.92 (1H, d, J = 8.8 Hz), 7.87 (1H, s), 7.76-7.62 (5H, m), 7.49-7.45 (1H, m), 7.36-7.26 (4H, m), 2.82 (3H, m) ESI (LC-MS modo positivo) 10 m/z 497 [(M+H)+j1H-NMR (DMSO-De) 8: 8.15-8.13 (2H, m), 8.02 (1H, dd, J = 8.4, 0.8 Hz), 7.97 (1H, d, J = 2.0 Hz), 7.92 (1H, d , J = 8.8 Hz), 7.87 (1H, s), 7.76-7.62 (5H, m), 7.49-7.45 (1H, m), 7.36-7.26 (4H, m), 2.82 (3H, m) ESI (LC -MS positive mode) 10 m / z 497 [(M + H) + j
Los compuestos de los números 1002 a 1082, y 1511 a 1527 enumerados en la Tabla 7, se sintetizaron mediante el mismo método como en la Etapa 1.The compounds of numbers 1002 to 1082, and 1511 to 1527 listed in Table 7, were synthesized by the same method as in Step 1.
Tabla 7Table 7
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1002 1002
- Q croKr v'ty- [5-amino-1-(2-metil-1H-bencimidazol-5-il)- IHpirazol- 1-il]- (1 -bencenosulfonil-6-morfolin-4-ilmetil-1 H-indol-2-il) metanona 596 Q croKr v'ty- [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) - I-pyrazol-1-yl] - (1-benzenesulfonyl-6-morpholin-4-ylmethyl-1 H- indole-2-yl) methanone 596
- 1003 1003
- ó a ácido 2-[5-amino-1-(2-metil-1H-bencimidazol-5-il)- IHpirazol-1 -carbonil]-1 -(tolueno-1 -sulfonil)-1 H-indol- 5- carboxílico 555 or to 2- [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) - I-pyrazol-1-carbonyl] -1 - (toluene-1-sulfonyl) -1 H-indole-5- carboxylic 555
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1004 1004
- 0 CüHL("* H [5-amino-1-(2-isopropil-1 H-bencimidazol-5-il)-1 Hpirazol- 1 -il]-[1-(tolueno-1 -sulfonil)-1 H-indol-2-il] -metanona 539 0 CüHL ("* H [5-amino-1- (2-isopropyl-1 H-benzimidazol-5-yl) -1 Hpyrazol-1-yl] - [1- (toluene-1-sulfonyl) -1 H- indole-2-yl] -methanone 539
- 1005 1005
- 0 ^3-0 v"'ar- [5-amino-1-(2-propil-1 H-bencimidazol-5-il)-1 Hpirazol-4- il]-[1-(tolueno-4-sulfonil)-1 H-indol-2-il] -metanona 539 0 ^ 3-0 v "'ar- [5-amino-1- (2-propyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4- yl] - [1- (toluene-4-sulfonyl) -1 H-indole-2-yl] -methanone 539
- 1006 1006
- OR^ ti [5-amino-1-(1H-bencimidazol-5-il)-1H-pi razol-4-il]-[1- (tolueno-4-sulfonil)-1H-indol-2-il]-metanona 497 OR ^ ti [5-amino-1- (1H-benzimidazol-5-yl) -1H-pi razol-4-yl] - [1- (toluene-4-sulfonyl) -1H-indole-2-yl] - methanone 497
- 1007 1007
- Q ^ [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpi razol-4-il]- (1-bencenosulfonN-5-morfoNn-4-NmetiMH-indol-2-il)- metanona 596 Q ^ [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpi razol-4-yl] - (1-benzenesulfonN-5-morphoNn-4-NmetiMH-indole-2-yl) - methanone 596
- 1008 1008
- Q o-¡fc_ 0 i"'€Cr [5-amino-1-(2-metil-1H-bencimidazol-5-1Hpirazol- 4-il]- (1-bencenosulfonil-4-morfolin-4-il -1 H-indol-2-il)- metanona 582 Q o-¡fc_ 0 i "'€ Cr [5-amino-1- (2-methyl-1H-benzimidazol-5-1 Hpyrazol-4-yl] - (1-benzenesulfonyl-4-morpholin-4-yl -1 H-indol-2-il) - methanone 582
- 1009 1009
- o °-¿í CO-L>-, o7 ^'tx-r [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpi razol-4-il]- (1-bencenosulfonil-4-morfolin-4-ilmetil-1H-indol-2-il)- metanona 596 or ° - ¿CO-L> -, o7 ^ 'tx-r [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1Hpi razol-4-yl] - (1-benzenesulfonyl -4-morpholin-4-ylmethyl-1H-indole-2-yl) - methanone 596
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1010 1010
- 0 ""-OH [5-amino-1-(2-trifluorometil-1H-bencimidazol-5-il) -1H- pirazol-4-il]-[1-(tolueno-4-sulfonil)-1H-indol-2-il]- metanona 565 0 "" -OH [5-amino-1- (2-trifluoromethyl-1H-benzimidazol-5-yl) -1H- pyrazol-4-yl] - [1- (toluene-4-sulfonyl) -1H-indole- 2-il] - methanone 565
- 1011 1011
- a^s'a'h [5-amino-1-(2-etil-1 H-bencimidazol-5-il)-1 Hpirazol-4-il]- [1-(tolueno-4-sulfonil)-1 H-indol-2-il] -metanona 525 a ^ s'a'h [5-amino-1- (2-ethyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4-yl] - [1- (toluene-4-sulfonyl) -1 H -indole-2-yl] -methanone 525
- 1012 1012
- tXHLf™4 V"'OTb [5-amino-1-(2-bencil-1 H-bencimidazol-5-il)-1 Hpirazol-4- il]-[1 -(tolueno-4-sulfonil)-1 H-indol-2-il] -metanona 587 tXHLf ™ 4 V "'OTb [5-amino-1- (2-benzyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4-yl] - [1 - (toluene-4-sulfonyl) -1 H -indole-2-yl] -methanone 587
- 1013 1013
- 0 h HN N-' [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpi razol-4- il]-(1-bencenosulfonil-5-pi perazin-1-ilmetil-1 H-indol-2-il)- metanona 595 0 h HN N- '[5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 Hpi razol-4-yl] - (1-benzenesulfonyl-5-pi perazin-1-ylmethyl-1 H-indol-2-il) - methanone 595
- 1014 1014
- _o p [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpi razol-4- il]-(1-bencenosulfonil-4-fluoro-1H-indol -2-il)-metanona 515 _o p [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpi razol-4-yl] - (1-benzenesulfonyl-4-fluoro-1H-indole -2-yl) -methanone 515
- 1015 1015
- *Q qC IL [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpi razol-4- il]-(1-bencenosulfonil-5-fluoro-1H-indol -2-il)-metanona 515 * Q qC IL [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpi razol-4- il] - (1-benzenesulfonyl-5-fluoro-1H-indole -2-yl) - methanone 515
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1016 1016
- Q p [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol-4- il]-(1-bencenosulfonil-6-fluoro-1H-indol -2-il)-metanona 515 Q p [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4- yl] - (1-benzenesulfonyl-6-fluoro-1H-indole -2-yl) - methanone 515
- 1017 1017
- ,P -■s=o C^aL1"* ^CGr H [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpirazol- 4- il]-(1-bencenosulfonil-1H-pirrolo[2,3-b] piridin-2-il)- metanona 498 , P - ■ s = o C ^ aL1 "* ^ CGr H [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 Hpirazol-4- yl] - (1-benzenesulfonyl-1 H- pyrrolo [2,3-b] pyridin-2-yl) - methanone 498
- 1018 1018
- 9 °fs=o oH-^ 'VNxPr [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpirazol- 4- il]-(1-bencenosulfonil-1H-pirrolo[3,2- c]piridin-2-il)- metanona 498 9 ° fs = or oH- ^ 'VNxPr [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpyrazol- 4- yl] - (1-benzenesulfonyl-1H-pyrrolo [3,2 - c] pyridin-2-yl) - methanone 498
- 1019 1019
- A CCCá-Lr ^’-CCr H [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpirazol- 4- il]-(1-bencenosulfonil-5-fluoro-6- morfolm-4-NmetiMH- indol-2-il)-metanona 614 A CCCá-Lr ^ '- CCr H [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpyrazol- 4- yl] - (1-benzenesulfonyl-5-fluoro-6- morfolm- 4-NmetiMH- indole-2-yl) -methanone 614
- 1020 1020
- ,0 cr^QXi* ‘""■0A [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpirazol- 4- il]-[1-bencenosulfonil-6-(2-morfolin-4-il-etoxi)-1H-indol- 2-il)-metanona 626 , 0 cr ^ QXi * '"" ■ 0A [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpyrazol- 4- yl] - [1-benzenesulfonyl-6- (2-morpholin) -4-yl-ethoxy) -1H-indole- 2-yl) -methanone 626
- 1021 1021
- o J:¿c O C-P*1. ^-op [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpirazol- 4- il]-[1-bencenosulfonil-6- tetrahidropiran -4-iloxi)-1H- indol-2-il)-metanona 597 or J: ¿C O C-P * 1. ^ -op [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpyrazol- 4- yl] - [1-benzenesulfonyl-6- tetrahydropyran -4-yloxy) -1H- indole-2 -il) -methanone 597
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1022 1022
- [5-amino-1-12-metil-1H-bencimidazol-5-il)-1Hpirazol- 4- il]-[4-cloro-1-(tolueno-4-sulfonil)- 1 H-indol- 2-il]- metanona 545, 547 [5-amino-1-12-methyl-1H-benzimidazol-5-yl) -1Hyrazol- 4- yl] - [4-chloro-1- (toluene-4-sulfonyl) - 1 H-indole-2-yl ] - methanone 545, 547
- 1023 1023
- Ó F t íg. ■J ,r OtT [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4- il]-[3-fluoro-1-(tolueno-4-sulfonil)-1 H-indol- 2-il]- metanona 529 Ó F t íg. ■ J, r OtT [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpyrazol- 4- yl] - [3-fluoro-1- (toluene-4-sulfonyl) - 1 H-indole-2-yl] - methanone 529
- 1024 1024
- Ó °£q r~XÉrL™> ^cr H [5-amino-1-(2-metil-1H-bencimidazol-5-il) 111- pirazol-4- il]-[5-(1-metil-piperidin-4-il)-1-(tolueno -4-sulfonil)-1H- indol-2-il]-metanona 608 Ó ° £ qr ~ XÉrL ™> ^ cr H [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) 111-pyrazol-4- yl] - [5- (1-methyl-piperidin- 4-yl) -1- (toluene -4-sulfonyl) -1H- indole-2-yl] -methanone 608
- 1025 1025
- 4 tert-butil éster del ácido 1-[2-[6-amino-1-(2-metil-1H- bencimidazol-5-il) -1H-pirazol-4-carbonil]-1-(tolueno-4- sulfonil)- 1H-indol-5-il]-3,6-dihidro-2H-piridina-1- carboxílico 692 4 tert-Butyl ester of 1- [2- [6-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-carbonyl] -1- (toluene-4-sulfonyl ) - 1H-indol-5-yl] -3,6-dihydro-2H-pyridine-1-carboxylic acid 692
- 1026 1026
- H tert -butil éster del ácido 4-[2-[5-amino-1-(2-metil-1H- bencimidazol-5-il) -1H-pirazol-4-carbonil]-1-(tolueno-4- sulfonil) -1H-indol-5-il]-piperidina-1-carboxílico 694 H tert -butyl ester of 4- [2- [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-carbonyl] -1- (toluene-4-sulfonyl ) -1H-indole-5-yl] -piperidine-1-carboxylic acid 694
- 1027 1027
- £ ■ojoí-C^ [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H -pirazol-4- il]-[5-((R)-3-fluoro-pirrolidin-1 -ilmetil) -1-(tolueno-4- sulfonil)-1H-indol-2-il]-metanona 612 £ ■ ojoí-C ^ [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H -pyrazol-4- yl] - [5 - ((R) -3-fluoro-pyrrolidin- 1-methylmethyl) -1- (toluene-4-sulfonyl) -1H-indole-2-yl] -methanone 612
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1028 1028
- tert-butil éster del ácido 4-[2-[5-amino-1-(2-metil-1H- bencimidazol-5-il) -1H-pirazol-4-carbonil]-6-fluoro-1- (tolueno-4- sulfonil)-1 H-indol-5-il]- piperidina-1- carbonílico 712 4- [2- [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1 H -pyrazol-4-carbonyl] -6-fluoro-1- (toluene-) tert-butyl ester 4- sulfonyl) -1 H-indole-5-yl] - piperidine-1-carbonyl 712
- 1029 1029
- r o0 V®‘ln H [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpirazol- 4- il]-[6-fluoro-5-(1-metil-piperidin-4-il) -1-(tolueno-4- sulfonil)-1H-indol-2-il]-metanona 626 r o0 V®'ln H [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 Hpirazol-4- yl] - [6-fluoro-5- (1-methyl-piperidin-4 -il) -1- (toluene-4-sulfonyl) -1H-indole-2-yl] -methanone 626
- 1030 1030
- P -0 üá-L- [5-imino-1-(2-metil-1H-bencimidazol-5-il)-1Hpirazol-4- il]-[1-bencenosulfonil-6-(tert-butildifenil-silaniloximetil)- 1 H-indol-2-il] metanona 765 P -0 üá-L- [5-imino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpyrazol-4- yl] - [1-benzenesulfonyl-6- (tert-butyldiphenyl-silanyloxymethyl) - 1 H-indol-2-yl] methanone 765
- 1031 1031
- í$ rr&S. ( yCT V-Q^ H [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol-4- il]-[5-(1-isopropil-piperidin-4-il)- 1-(tolueno-4-sulfonil)- 1 H-indol-2-il]-metanona 636 í $ rr & S. (yCT VQ ^ H [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4- yl] - [5- (1-isopropyl-piperidin-4-yl) - 1- (toluene-4-sulfonyl) - 1 H-indol-2-yl] -methanone 636
- 1032 1032
- 3SO H [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol-4- il]-[6-fuloro-5-(1-isopropil-piperidin-4-il) -1-(tolueno-4- sulfonil)-1H-indol-2-il]-metanona 654 3SO H [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4- yl] - [6-fuloro-5- (1-isopropyl-piperidin-4-yl) -1- (toluene-4-sulfonyl) -1H-indole-2-yl] -methanone 654
- 1033 1033
- jV.J [5-amino-1-(2-metil-1H-bencimidazol-1-il)-1Hpirazol-4- il]-{1-bencenosulfonil-6-[2-(4-metilpiperidin-1-il)-etoxi]- 1 H-indol-2-il}-metanona 639 jV.J [5-amino-1- (2-methyl-1H-benzimidazol-1-yl) -1Hpyrazol-4- yl] - {1-benzenesulfonyl-6- [2- (4-methylpiperidin-1-yl) -ethoxy] - 1 H-indol-2-yl} -methanone 639
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1034 1034
- P ■<arxxh0^ H [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4- il]-[6-fluoro-5-(4-metil-piperadin-1-ilmetil)-1-(tolueno-4- sulfonil)-1H-indol-2-il]-metanona 641 P ■ <arxxh0 ^ H [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpyrazol- 4- yl] - [6-fluoro-5- (4-methyl-piperadin- 1-ylmethyl) -1- (toluene-4-sulfonyl) -1H-indole-2-yl] -methanone 641
- 1035 1035
- P V'yVV [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol-4- il]-[6-fluoro-5-pirrolidin-1-ilmetil- 1-(tolueno-4-sulfonil)- 1 H-indol-2-il]-metanona 612 P V'yVV [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4- yl] - [6-fluoro-5-pyrrolidin-1-ylmethyl- 1- ( toluene-4-sulfonyl) - 1 H-indol-2-yl] -methanone 612
- 1036 1036
- i Q «Xír [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4- il]--[6-(1-metil-piperidin-4-il)- 1-(tolueno-4-sulfonil)-1H- indol-2-il]-metanona 608 i Q «Xír [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpyrazol- 4- yl] - [6- (1-methyl-piperidin-4-yl) - 1- (toluene-4-sulfonyl) -1H- indole-2-yl] -methanone 608
- 1037 1037
- £ [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol-4- il]-[5-(4-fluoro-piperidin-1-ilmetil)-1-(tolueno-4-sulfonil)- 1 H-indol-2-il]-metanona 626 £ [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4- yl] - [5- (4-fluoro-piperidin-1-ylmethyl) -1- (toluene -4-sulfonyl) - 1 H-indol-2-yl] -methanone 626
- 1038 1038
- P H [5-amino-1-(2-difluorometil-1H-bencimidazol-5-il) -1H- pirazol-4-il]-[5-(1-metil-piperidin-4-il)- 1-(tolueno-4- sulfonil)-1H-indol-2-il]-metanona 644 PH [5-amino-1- (2-difluoromethyl-1 H -benzimidazol-5-yl) -1 H- pyrazol-4-yl] - [5- (1-methyl-piperidin-4-yl) - 1- (toluene -4- sulfonyl) -1H-indole-2-yl] -methanone 644
- 1039 1039
- $ °«0A o hl [5-amino-1-(2-difluorometil-1H-bencimidazol-5-il) -1H- pirazol-4-il]-[1-(tolueno-4-sulfonil)-1 H-indol -2-il]- metanona 547 0 ° or hl [5-amino-1- (2-difluoromethyl-1 H -benzimidazol-5-yl) -1 H- pyrazol-4-yl] - [1- (toluene-4-sulfonyl) -1 H- indole -2-il] - methanone 547
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1040 1040
- í [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H pirazol-4- il]-[5-(1-ciclopentil-piperidin-4-il)- 1-(tolueno-4-sulfonil)- 1 H-indol-2-il]-metanona 662 í [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H pyrazol-4- yl] - [5- (1-cyclopentyl-piperidin-4-yl) - 1- (toluene- 4-sulfonyl) - 1 H-indol-2-yl] -methanone 662
- 1041 1041
- i [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol-4-il]- [5-(1-ciclohexil-piperidin-4-il)- 1-(tolueno-4-sulfonil)-1H- indol-2-il]-metanona 676 i [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4-yl] - [5- (1-cyclohexyl-piperidin-4-yl) - 1- (toluene -4-sulfonyl) -1H- indole-2-yl] -methanone 676
- 1042 1042
- <> 0jT’ P B» [5-amino-1-(2-metil-1 H-bencimidaml-5-il)-1 Hpi razol-4-il]- [4-bromo-1-(tolueno-4-sulfonil)-1Hpirrol-2-il]-metanona 539, 541 <> 0jT 'PB »[5-amino-1- (2-methyl-1 H-benzimidaml-5-yl) -1 Hpi razol-4-yl] - [4-bromo-1- (toluene-4-sulfonyl ) -1Hpirrol-2-yl] -methanone 539, 541
- 1043 1043
- ~Á- 1 F1 u [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol-4-il]- [1-(tolueno-4-sulfonil)-1H-pirrol-2-il]-metanona 461 ~ Á- 1 F1 u [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4-yl] - [1- (toluene-4-sulfonyl) -1H-pyrrole -2-il] -methanone 461
- 1044 1044
- '^Cá-L* Ws-r [5-amino-1-(2-metil-1 H-bencimidazol-5-il)1Hpi razol-4-il]- [6-butil-1-(tolueno-4-sulfonil)-1H-indol-2-il]-metanona 567 '^ Cá-L * Ws-r [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) 1Hpi razol-4-yl] - [6-butyl-1- (toluene-4- sulfonyl) -1H-indole-2-yl] -methanone 567
- 1045 1045
- F £ ¡k^°o y-J v-ctV [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpirazol- 4- il]-[5-(1-isopropil-piperidin-4-il)- 1-(tolueno-4-sulfonil)-6- trifluorometil-1H-indol-2-il]-metanona 704 F £ ¡k ^ ° or yJ v-ctV [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpyrazol- 4- yl] - [5- (1-isopropyl-piperidin-4 -yl) - 1- (toluene-4-sulfonyl) -6- trifluoromethyl-1H-indole-2-yl] -methanone 704
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1046 1046
- 0 3 " Y 'r""' r _/' [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4- il]-6-bromo-1-(tolueno-4-sulfonil)-1H-indol- 2-il- metanona 589, 591 0 3 "Y 'r" "' r _ / '[5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpyrazol- 4- yl] -6-bromo-1- ( toluene-4-sulfonyl) -1H-indole-2-yl-methanone 589, 591
- 1047 1047
- ó [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4- il]-[6-ciclopropil-1-(tolueno-4-sulfonil) -1 H-indol-2-il]- metanona 551 or [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpyrazol- 4- yl] - [6-cyclopropyl-1- (toluene-4-sulfonyl) -1 H-indole -2-il] - methanone 551
- 1048 1048
- $ JC&L* [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4- il]-[5-bromo-1-(tolueno-4-sulfonil)-1H-indol- 2-il]- metanona 589, 591 JC & L * [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpyrazol- 4- yl] - [5-bromo-1- (toluene-4-sulfonyl) -1H- indole-2-il] - methanone 589, 591
- 1049 1049
- ó pC0,“i ■ [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4- il]-[4-yodo-1-(tolueno-4-sulfonil)-1H-indol- 2-il]- metanona 637 or pC0, "i ■ [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpyrazol- 4- yl] - [4-iodo-1- (toluene-4-sulfonyl) -1H-indole- 2-yl] - methanone 637
- 1050 1050
- ,0 [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4- il]-[6-isopropil-1-(tolueno-4-sulfonil)-1 H-indol- 2-il]- metanona 553 , 0 [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpyrazol- 4- yl] - [6-isopropyl-1- (toluene-4-sulfonyl) -1 H- indole-2-yl] - methanone 553
- 1051 1051
- 9 Y-O 0300"’ % [5-amino-1-12-metil-1H-bencimidazol-5-il)-1Hpirazol- 4- il]-(1-bencenosulfonil-1H-pirrolo[3,2- b]piridin-2-il)- metanona 498 9 YO 0300 "'% [5-amino-1-12-methyl-1 H -benzimidazol-5-yl) -1 Hpirazol-4- yl] - (1-benzenesulfonyl-1 H -pyrrolo [3,2- b] pyridine- 2-il) - methanone 498
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1052 1052
- " JL 1 e %xs>- h [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpi razol- 4-il]-[5-bromo-1-(tolueno-4-sulfonil)-6- trifluorometil- 1 H-indol-2-il]-metanona 657,659 "JL 1 e% xs> - h [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpi razol-4-yl] - [5-bromo-1- (toluene-4- sulfonyl) -6- trifluoromethyl- 1 H-indol-2-yl] -methanone 657,659
- 1053 1053
- Q i* &r-0HJ ^ f [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpi razol- 4-il]-[6-bromo-5-fluoro-1-(tolueno-4- sulfonil)-1H- indol-2-il]-metanona 607,609 Q i * & r-0HJ ^ f [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpi razol-4-yl] - [6-bromo-5-fluoro-1- (toluene -4- sulfonyl) -1H- indole-2-yl] -methanone 607,609
- 1054 1054
- fS O MT¿kr [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpi razol- 4-il]-[6-piridin-2-il-1 -(tolueno-4-sulfonil)-1 H-indol-2-il]- metanona 588 fS O MT¿kr [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpi razol-4-yl] - [6-pyridin-2-yl-1 - (toluene-4- sulfonyl) -1 H-indole-2-yl] - methanone 588
- 1055 1055
- ó -XXH,*- H [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpi razol- 4-il]-[5-ciclopropil-1-(tolueno-4-sulfonil) -1 H-indol-2-il]- metanona 551 or -XXH, * - H [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpi razol-4-yl] - [5-cyclopropyl-1- (toluene-4-sulfonyl) -1 H-indole-2-yl] - methanone 551
- 1056 1056
- $ n *jz.. EK [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpi razol- 4-il]-[6-piridazin-3-il-1 -(tolueno-4- sulfonil) -1 H-indol- 2-il]-metanona 589 $ n * jz .. EK [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpi razol-4-yl] - [6-pyridazin-3-yl-1 - (toluene- 4- sulfonyl) -1 H-indole-2-yl] -methanone 589
- 1057 1057
- XcR/-. 9,txr [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpi razol- 4-il]-[6-metilsulfanil-1 -(tolueno-4- sulfonil) -1 H-indol-2- il]-metanona 557 XcR / -. 9, txr [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1Hpi razol-4-yl] - [6-methylsulfanyl-1 - (toluene-4-sulfonyl) -1 H- indole-2- il] -methanone 557
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1058 1058
- Ó .xxJ^ ?kar [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpirazol- 4- il]-[5-bromo-1-(tolueno-4-sulfonil)-1H-indol- 2-il]- metanona 589, 591 Ó .xxJ ^? Kar [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hyrazol- 4- yl] - [5-bromo-1- (toluene-4-sulfonyl) -1H -indol- 2-il] - methanone 589, 591
- 1059 1059
- h [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpirazol- 4- il]-[5-butoxi-1-(tolueno-4-sulfonil)-1H-indol- 2-il]- metanona 583 h [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1-pyrazol- 4- yl] - [5-butoxy-1- (toluene-4-sulfonyl) -1H-indole-2- il] - methanone 583
- 1060 1060
- i O'S-o [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpirazol- 4- il]-[5-isopropoxi-1-(tolueno-4-sulfonil)- 1 H-indol-2-il]- metanona 569 i O'S-o [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 Hpirazol-4- yl] - [5-isopropoxy-1- (toluene-4-sulfonyl) - 1 H- indole-2-il] - methanone 569
- 1061 1061
- 5 ,'VlJ yo [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpirazol- 4- il]-[5-(2-metoxi-etoxi)-1-(tolueno-4- sulfonil)-1 H-indol-2- il]-metanona 585 5, 'VlJ yo [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hyrazol- 4- yl] - [5- (2-methoxy-ethoxy) -1- (toluene-4 - sulfonyl) -1 H-indole-2-yl] -methanone 585
- 1062 1062
- «i? ^txr H [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpirazol- 4- il]-(1-bencenosulfonil-4-metil-1H-indol -2-il)-metanona 511 «I? ^ txr H [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpyrazol- 4- yl] - (1-benzenesulfonyl-4-methyl-1H-indole -2-yl) -methanone 511
- 1063 1063
- p 0*3=0 1 WXr H [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpirazol- 4- il]-(-(1-bencenosulfonil-4- trimetilsilanileti nil-1 H-indol-2- il]-]metanona 593 p 0 * 3 = 0 1 WXr H [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpyrazol- 4- yl] - (- (1-benzenesulfonyl-4- trimethylsilanileti nil-1 H-indol-2- il] -] methanone 593
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1064 1064
- ■i íxc.r [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpi razol- 4-il]-[5-(tolueno-4-sulfonil)-5H-[1,3] dioxolo[4,5-f]indol- 6-il]-metanona 555 ■ i xc.r [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpi razol-4-yl] - [5- (toluene-4-sulfonyl) -5H- [1, 3] dioxolo [4,5-f] indole-6-yl] -methanone 555
- 1065 1065
- »Xtr H [5-amino-1-(2-metil-1H-bencimidazol-5-il)-IHpirazol- 4- il]-[5-cidopropilmetoxi-1-(tolueno-4- sulfonil)-1 H-indol- 2-il]-metanona 581 »Xtr H [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -IHpirazol-4- yl] - [5-cidopropylmethoxy-1- (toluene-4-sulfonyl) -1 H-indole - 2-yl] -methanone 581
- 1066 1066
- 0 0—S=0 9 NH7 ij^Y^ Sr [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpi razol- 4-il]-(1-bencenosulfonil-4-bromo-1H-indol- 2-il]- metanona 575, 577 0 0 — S = 0 9 NH7 ij ^ Y ^ Sr [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpi razol-4-yl] - (1-benzenesulfonyl-4-bromo -1H-indole-2-yl] - methanone 575, 577
- 1067 1067
- Ó _ 0*cA H [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpi razol- 4-il]-[2,2-difluoro-5-(tolueno-4-sulfonil)- 5H- [1,3]dioxolo[4,5-f]indol-6-il]-metanona 591 Ó _ 0 * cA H [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpi razol-4-yl] - [2,2-difluoro-5- (toluene-4-sulfonyl ) - 5H- [1,3] dioxolo [4,5-f] indole-6-yl] -methanone 591
- 1068 1068
- rrci $ VTXH^ [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpi razol- 4-il]-[6-(3-cloropiridin-2-il)-1 -(tolueno-4- sulfonil)-1H- indol-2-il]-metanona 622 rrci VTXH ^ [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpi razol-4-yl] - [6- (3-chloropyridin-2-yl) -1 - (toluene -4- sulfonyl) -1H- indole-2-yl] -methanone 622
- 1069 1069
- 1—\ wj [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpi razol- 4-il]-[6-(3-fluoro-piridin-2-il)-1-(tolueno-4- sulfonil)-1H- indol-2-il]-metanona 606 1— [w-[5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 Hpi razol-4-yl] - [6- (3-fluoro-pyridin-2-yl) -1- (toluene-4-sulfonyl) -1H- indole-2-yl] -methanone 606
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1070 1070
- 9 CÍH-,". f h [5-amino-1-(7-fluoro-2-metil-1H-bencimidazol -5-il)-1H- pirazol-4-il]-(1-bencenosulfonil-1H-indol- 2-il)- metanona 515 9 CÍH-, ". Fh [5-amino-1- (7-fluoro-2-methyl-1H-benzimidazol -5-yl) -1H- pyrazol-4-yl] - (1-benzenesulfonyl-1H-indole- 2-il) - methanone 515
- 1071 1071
- ■0 'H-O C , j = í j 'i tr^ [5-amino-1-(2-metiMH-bencimidazol-5-N)-1Npirazol- 4- il]-[6-metil-1-(tolueno-4-sulfonil)-1H-indol- 2-il]- metanona 525 ■ 0 'HO C, j = í j' i tr ^ [5-amino-1- (2-metiMH-benzimidazol-5-N) -1Npyrazol- 4- yl] - [6-methyl-1- (toluene- 4-sulfonyl) -1H-indole-2-yl] - methanone 525
- 1072 1072
- ■o¿. [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4- il]-[6-(5-fluoro-piridin-2-il)-1-(tolueno-4- sulfonil)-1H- indol-2-il]-metanona 606 ■ or ¿. [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpyrazol- 4- yl] - [6- (5-fluoro-pyridin-2-yl) -1- (toluene- 4- sulfonyl) -1H- indole-2-yl] -methanone 606
- 1073 1073
- [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pi razol- 4-il]-[6-(6-morfolin-4-il-piridazin-3-il) -1-(tolueno-4- sulfonil)-1H-indol-2-il]-metanona 674 [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H-pi razol-4-yl] - [6- (6-morpholin-4-yl-pyridazin-3-yl ) -1- (toluene-4-sulfonyl) -1H-indole-2-yl] -methanone 674
- 1074 1074
- 0 fr-cd- [5-amino-1-(2-metil-1H-bencimidazol-5-il) -111 pirazol- 4- il]-[5-cloro-6-ciclopropilmetil- 1-(tolueno-4-sulfonil) -1H- indol-2-il]-metanona 615, 617 0 fr-cd- [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -111 pyrazol- 4- yl] - [5-chloro-6-cyclopropylmethyl- 1- (toluene-4- sulfonyl) -1H- indole-2-yl] -methanone 615, 617
- 1075 1075
- fjXX aR.- Qxxr [5-amino-1-(2-metil-1H-bencimidazol-5-il) -1Hpirazol- 4-il]-[1-(tolueno-4-sulfonil)-6-(5- trifluorometil-piridin-2- il)-1 H-indol-2-il] -metanona 656 fjXX aR.- Qxxr [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpirazol- 4-yl] - [1- (toluene-4-sulfonyl) -6- (5- trifluoromethyl -pyridin-2-yl) -1 H-indol-2-yl] -methanone 656
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1076 1076
- . $$ ®--&r [5-amino-1-(2-metil-1H-bencimidazol-5-il) -1Hpirazol- 4-il]-[1-(tolueno-4-sulfonil)-6-(6- tritluorometil-piridizi-2- il)-1 H-indol-2-il] -metanona 656 . $$ ® - & r [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 Hpirazol-4-yl] - [1- (toluene-4-sulfonyl) -6- (6- tritluoromethyl-pyridizi-2- yl) -1 H-indol-2-yl] -methanone 656
- 1077 1077
- ■■ $ ~r\ [5-amino-1-(2-metil-1H-bencimidazol-5-il) -1Hpirazol- 4-il]-[6-(5-cloro-piridin-2-il)-1-(tolueno- 4-sulfonil)-1H- indol-2-il]-metanona 621, 623 ■■ $ ~ r \ [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 Hpirazol-4-yl] - [6- (5-chloro-pyridin-2-yl) -1 - (toluene- 4-sulfonyl) -1H- indole-2-yl] -methanone 621, 623
- 1078 1078
- >ír vXír [5-amino-1-(2-metil-1H-bencimidazol-5-il) -1Hpirazol- 4-il]-[4,5-dibromo-1-(4-metoxibencil)- 1 H-pi rrol-2-il]- metanona 583, 585, 587 > ír vXír [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 Hpirazol-4-yl] - [4,5-dibromo-1- (4-methoxybenzyl) - 1 H-pi rrol-2-il] - methanone 583, 585, 587
- 1079 1079
- [5-amino-1-(2-metil-1H-bencimidazol-5-il) -1Hpirazol- 4-il]-[1-(tolueno-4-sulfonil)-6-(5- tritluorometil-1-piridin- 2-il)-1 H-indol-2-il] -metanona 656 [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1-pyrazol-4-yl] - [1- (toluene-4-sulfonyl) -6- (5- tritluoromethyl-1-pyridin- 2-yl) -1 H-indole-2-yl] -methanone 656
- 1080 1080
- K í 'Tk,- [5-amino-1-(2-metil-1H-bencimidazol-5-il) -1Hpirazol- 4-il]-[1-(tolueno-4-sulfonil)-6-(4- trifluorometil-piridin-2- il)-1 H-indol-2-il] -metanona 656 K í 'Tk, - [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hyrazol- 4-yl] - [1- (toluene-4-sulfonyl) -6- (4- trifluoromethyl-pyridin-2- yl) -1 H-indol-2-yl] -methanone 656
- 1081 1081
- 9 [5-amino-1-(7-fluoro-2-metil-1H-bencimidazol-il)- 1H- pirazol-4-il]-(1-bencenosulfonil-1H-indol- 2-il)- metanona 515 9 [5-amino-1- (7-fluoro-2-methyl-1H-benzimidazol-yl) -1H-pyrazol-4-yl] - (1-benzenesulfonyl-1H-indole-2-yl) -methanone 515
- 1082 1082
- .P Go<j* x- <5tx¡r [5-amino-1-(2-metil-1H-bencimidazol-5-il) -1Hpirazol- 4-il]-(1-bencenosulfonil-4-isopropil-1H-indol- 2-il]- metanona 539 .P Go <j * x- <5tx¡r [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpyrazol-4-yl] - (1-benzenesulfonyl-4-isopropyl-1H -indol- 2-il] - methanone 539
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1511 1511
- ■i 0 , y J- *0 -s O HH„ J i [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4-il]-[6-cloro-1-(tolueno-4-sulfonil)- 1 H-indol-2-il]- metanona 545 ■ i 0, and J- * 0 -s O HH „J i [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4-yl] - [6-chloro -1- (toluene-4-sulfonyl) - 1 H-indole-2-yl] - methanone 545
- 1512 1512
- í p [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4-il]-[6-cloro-1-(tolueno-4-sulfonil)- 1 H-indol-2-il]- metanona 545 í p [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 Hpyrazol-4-yl] - [6-chloro-1- (toluene-4-sulfonyl) - 1 H- indole-2-il] - methanone 545
- 1513 1513
- ^nVT<nh V [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4-il]-[1-(tolueno-4-sulfonil)-1H-indol-3-il]-metanona 511 ^ nVT <nh V [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4-yl] - [1- (toluene-4-sulfonyl) -1H-indole- 3-il] -methanone 511
- 1514 1514
- OS 0 [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4-il]-[1-(tolueno-4-sulfonil)-1H-indol-6-il]-metanona 511 OS 0 [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4-yl] - [1- (toluene-4-sulfonyl) -1H-indole-6-yl ] -methanone 511
- 1515 1515
- & ^-cír [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4-il]-[5-bromo-6-fluoro-1-(tolueno-4-sulfonil)-1H-indol- 2-il]-metanona 607 & ^ -cír [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4-yl] - [5-bromo-6-fluoro-1- (toluene-4- sulfonyl) -1H-indole-2-yl] -methanone 607
- 1516 1516
- / <£ ’S'° [5-amino-1-(2-etil-1 H-bencimidazol-5-il)-1 Hpirazol- 4- il]-[5-bromo-6-fluoro-1-(tolueno-4- sulfonil)-1 H-indol- 2-il]-metanona 621 / <£ 'S' ° [5-amino-1- (2-ethyl-1 H-benzimidazol-5-yl) -1 Hpyrazol- 4- yl] - [5-bromo-6-fluoro-1- (toluene -4- sulfonyl) -1 H-indole- 2-yl] -methanone 621
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1517 1517
- •g-0 f H [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4-il]-[1-(tolueno-4-sulfonil)-5- trifluorometil-1 H-indol-2- il]-metanona 579 • g-0 f H [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4-yl] - [1- (toluene-4-sulfonyl) -5- trifluoromethyl -1 H-indole-2- il] -methanone 579
- 1518 1518
- é H [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4-il]-[1-(tolueno-4-sulfonil)-5- trifluorometoxMH-mdol- 2-il]-metanona 595 é H [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpirazol- 4-yl] - [1- (toluene-4-sulfonyl) -5- trifluoromethoxMH-mdol- 2 -il] -methanone 595
- 1519 1519
- d Q, 5^ 0 LLH,nh3 C, H [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4-il]-[4,6-dicloro-1-(tolueno-4- sulfonil)-1 H-ind ol-2-il]- metanona 579 d Q, 5 ^ 0 LLH, nh3 C, H [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4-yl] - [4,6-dichloro-1 - (toluene-4-sulfonyl) -1 H-ind ol-2-il] - methanone 579
- 1520 1520
- ó 'XO-L^ [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4-il]-[6-bromo-4-fluoro-1-(tolueno-4- sulfonil)-1H- indol-2-il]-metanona 607 or 'XO-L ^ [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4-yl] - [6-bromo-4-fluoro-1- (toluene- 4- sulfonyl) -1H- indole-2-yl] -methanone 607
- 1521 1521
- d F-fF ^hocv [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4-il]-[1-(tolueno-4-sulfonil)-6- trifluorometoxi-1H-indol- 2-il]-metanona 595 d F-fF ^ hocv [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpyrazol- 4-yl] - [1- (toluene-4-sulfonyl) -6- trifluoromethoxy -1H-indole- 2-yl] -methanone 595
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1522 1522
- A & vXCr. • H [5-amino-1-(2-etil-1 H-bencimidazol-5-il)-1 Hpirazol- 4-il]-[1-(tolueno-4-sulfonil)-5- trifluorometoxi-1H- indol-2-il]-metanona 609 A & vXCr. • H [5-amino-1- (2-ethyl-1 H-benzimidazol-5-yl) -1 Hpyrazol-4-yl] - [1- (toluene-4-sulfonyl) -5- trifluoromethoxy-1H-indole -2-il] -methanone 609
- 1523 1523
- $ °To N F H [5-amino-1-(2-etil-1 H-bencimidazol-5-il)-1 Hpirazol- 4-il]-[1-(tolueno-4-sulfonil)-5- trifluorometil-1 H-indol- 2-il]-metanona 593 To NFH [5-amino-1- (2-ethyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4-yl] - [1- (toluene-4-sulfonyl) -5- trifluoromethyl-1 H-indole-2-yl] -methanone 593
- 1524 1524
- s-° L L/ix NH, W a ^XXlr H [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4-il]-[5,6-dicloro-1-(tolueno-4- sulfonil)-1 H-indol-2-il]- metanona 579 s- ° LL / ix NH, W a ^ XXlr H [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4-yl] - [5,6-dichloro- 1- (toluene-4-sulfonyl) -1 H-indol-2-yl] - methanone 579
- 1525 1525
- ¡k Br>-ríí>vr-N O F CÍ'Ox H [5-amino-1-(2-etil-1 H-bencimidazol-5-il)-1 Hpirazol- 4-il]-[6-bromo-5-fluoro-1-(tolueno-4- sulfonil)-1H- indol-2-il]-metanona 621 ¡Br> -rí> vr-N OF CÍ'Ox H [5-amino-1- (2-ethyl-1 H-benzimidazol-5-yl) -1 Hpirazol- 4-yl] - [6-bromo- 5-fluoro-1- (toluene-4- sulfonyl) -1H- indole-2-yl] -methanone 621
- 1526 1526
- £ °ñ L JU^X Ni, cr^f >■=( a N'Ntxr H [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4-il]-[4,5-dicloro-1-(tolueno-4- sulfonil)-1 H-indol-2-il]- metanona 579 £ ° ñ L JU ^ X Ni, cr ^ f> ■ = (a N'Ntxr H [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4-yl] - [4,5-dichloro-1- (toluene-4-sulfonyl) -1 H-indol-2-yl] - methanone 579
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1527 1527
- s-O [5-amlno-1-(2-metll-1 H-bencimidazol-5-¡l)-1 Hpirazol- 4-¡ l]-[4,6-dif I uoro-1 -(tol u e n o-4- sulfonil)-1 H-indol-2- il]-metanona 547 sO [5-amlno-1- (2-metll-1 H-benzimidazol-5-¡l) -1 Hpirazol- 4-l] - [4,6-dif I uoro-1 - (tol uen o-4 - sulfonyl) -1 H-indole-2-yl] -methanone 547
[Ejemplos 165 a 195, y 247 a 254][Examples 165 to 195, and 247 to 254]
Los compuestos de los Ejemplos 165 a 195, y 247 a 254 enumerados en la Tabla 8, se sintetizaron utilizando los 5 compuestos que tienen un anillo indol con átomos de nitrógeno sin proteger, mediante el mismo método como en la Etapa 1.The compounds of Examples 165 to 195, and 247 to 254 listed in Table 8, were synthesized using the 5 compounds having an indole ring with unprotected nitrogen atoms, by the same method as in Step 1.
Tabla 8Table 8
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 165 165
- M i*™, —Q [5-amlno-1-(2-metil-1 H- benclmldazol- 5-II)- 1 Hpirazol- 4-il] -(5- metoxl-1 H-indol-2-il)- metanona 387 1H-RMN (DMSO-D6) 6: 12.47 (1H, s), 11.56 (1H, s), 8.27 (1H, s), 7.62 (2H, s), 7.39-7.35 (2H, mi, 7.29 (1H, dd, J = 8.5, 1.8 Hz), 7,13 (1H, d, J = 2.4 Hz), 6.99 (2H, s), 6.99 (1H, dd, J = B.5, 2.4 Hz), 3.78 (3H, s), 2.53 (3H, s). M i * ™, —Q [5-amlno-1- (2-methyl-1 H- benclmldazol-5-II) - 1 Hpirazol-4-yl] - (5- methoxl-1 H-indole-2-yl ) - methanone 387 1H-NMR (DMSO-D6) 6: 12.47 (1H, s), 11.56 (1H, s), 8.27 (1H, s), 7.62 (2H, s), 7.39-7.35 (2H, mi, 7.29 (1H, dd, J = 8.5, 1.8 Hz), 7.13 (1H, d, J = 2.4 Hz), 6.99 (2H, s), 6.99 (1H, dd, J = B.5, 2.4 Hz) , 3.78 (3H, s), 2.53 (3H, s).
- 166 166
- v*-cCr [-amlno-1-(2-metll-1H- benclmldazol- 5-il)- 1 Hpirazol- 4-il] -(4,6- dlmetoxl-1 H-lndol-2-il)- metanona 417 1H-RMN (DMSO-D6) 6: 12.46 (1H, s), 11.66 (1H, d, J = 1.8 Hz), 8.22 (1H, s), 7.62-7.57 (2H, m), 7.31-7.28 (1H, m), 7.25 (1H, d, J = 1.8 Hz), 6.92 (2H, d, J = 22.0 Hz), 6.53 (1H, s), 6.21 (1H, d, J = 1.3 Hz), 3.88 (3H, s), 3.79 (3H, s), 2.53 (3H, s). v * -cCr [-amlno-1- (2-metll-1H- benclmldazol- 5-yl) - 1 Hpirazol- 4-yl] - (4,6- dlmethoxl-1 H-lndol-2-yl) - methanone 417 1H-NMR (DMSO-D6) 6: 12.46 (1H, s), 11.66 (1H, d, J = 1.8 Hz), 8.22 (1H, s), 7.62-7.57 (2H, m), 7.31-7.28 ( 1H, m), 7.25 (1H, d, J = 1.8 Hz), 6.92 (2H, d, J = 22.0 Hz), 6.53 (1H, s), 6.21 (1H, d, J = 1.3 Hz), 3.88 ( 3H, s), 3.79 (3H, s), 2.53 (3H, s).
- 167 167
- [5-amlno-1-(2-metll-1 H- benclmldazol- 5-II)- 1 Hpirazol-4 -il] -(4- metoxl-1 H-indol-2-il)- metanona 387 1H-RMN (DMSO-D6) 6: 12.47 (1H, s), 11.73 (1H, s), 8.25 (1H, s), 7.62-7.60 (2H, m), 7.32-7.28 (2H, m), 7.18 (1H, dd, J = 7.9, 4.0 Hz), 7.07 (1H, d, J = 8.5 Hz), 6.98 (2H, s), 6.55 (1H, d, J = 7.3 Hz), 3.92 (3H, s), 2.53 (3H, s). [5-amlno-1- (2-metll-1 H- benclmldazol-5-II) - 1 Hpirazol-4-yl] - (4- methoxl-1 H-indole-2-yl) - methanone 387 1 H-NMR (DMSO-D6) 6: 12.47 (1H, s), 11.73 (1H, s), 8.25 (1H, s), 7.62-7.60 (2H, m), 7.32-7.28 (2H, m), 7.18 (1H, dd, J = 7.9, 4.0 Hz), 7.07 (1H, d, J = 8.5 Hz), 6.98 (2H, s), 6.55 (1H, d, J = 7.3 Hz), 3.92 (3H, s), 2.53 ( 3H, s).
- 168 168
- [5-amino-1-(2-metll-1 H- bencimldazol- 5-II)- 1 Hpirazol- 4-il] -(6- metoxi-1 H-indol-2-il)- metanona 387 1H-RMN (DMSO-D6) 8: 12.46 (1H, s), 11.53 (1H, s), 8.28 (1H, s), 7.60-7.57 (3H, mi), 7.41 (1H, d. J = 1.8 Hz), 7.29 (1H, dd, J = 8.5, 1.8 Hz), 6.95-6.93 (3H, m), 6.75 (1H, dd, J = 8.9, 2.1 Hz), 3.80 (3H, s), 2.53 (3H, s). [5-amino-1- (2-metll-1 H- benzimldazol-5-II) - 1 Hpirazol-4-yl] - (6- methoxy-1 H-indole-2-yl) - methanone 387 1 H-NMR (DMSO-D6) 8: 12.46 (1H, s), 11.53 (1H, s), 8.28 (1H, s), 7.60-7.57 (3H, mi), 7.41 (1H, d. J = 1.8 Hz), 7.29 (1H, dd, J = 8.5, 1.8 Hz), 6.95-6.93 (3H, m), 6.75 (1H, dd, J = 8.9, 2.1 Hz), 3.80 (3H, s), 2.53 (3H, s).
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 169 169
- T [5-amino-1-(2-metil-1H- bencimidazol- 5-il)- IHpirazol- 4-11] -(4,6- dlmetil-1 H-indol-2-il)- metanona 385 1H-RMN (DMSO-D6) 8: 12.46 (1H, s), 11.51 (1H, s), 8.37 (1H, s), 7.65-7.57 (2H, br m), 7.40 (1H, br s), 7.29 (1R, d, J = 8.5 Hz), 7.07 (1H, br s), 6.96 (2H, br s), 6.70 (1H, br s), 2.53 (3H, s), 2.53 (3H, s), 2.37 (3H, s). T [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) - I-pyrazol-4-11] - (4,6-dlmethyl-1 H-indol-2-yl) - methanone 385 1H- NMR (DMSO-D6) 8: 12.46 (1H, s), 11.51 (1H, s), 8.37 (1H, s), 7.65-7.57 (2H, br m), 7.40 (1H, br s), 7.29 (1R , d, J = 8.5 Hz), 7.07 (1H, br s), 6.96 (2H, br s), 6.70 (1H, br s), 2.53 (3H, s), 2.53 (3H, s), 2.37 (3H , s).
- 170 170
- yC&'Om, * ■“* H [5-amino-1-(2-metil-1H- bencimidazol- 5-il)- IHpirazol- 4-¡l] -(5-tert- butil-1 H-indol-2-M)- metanona 413 1H-RMN (DMSO-D6) 8: 12.46 (1H, s), 11-55 (1H, s), 8.27 (1H, s), 7.64-7.58 (2H, br m), 1.63 (1H, d, J = 1.5 Hz), 7.41 (1H, d, J = 8.5 Hz), 7.40 (1H, s), 7.36 (1H, dd, J = 8.5, 1.5 Hz). 7.29 (1H, dd, J = 8.5, 1.8 Hz), 6.99 (2H, br s), 2.53 (3H, d, J = 4.3 Hz), 1.35 (9H, s), yC & 'Om, * ■ “* H [5-amino-1- (2-methyl-1H- benzimidazol-5-yl) - IHpyrazol- 4-yl] - (5-tert-butyl-1 H-indole- 2-M) - methanone 413 1H-NMR (DMSO-D6) 8: 12.46 (1H, s), 11-55 (1H, s), 8.27 (1H, s), 7.64-7.58 (2H, br m), 1.63 (1H, d, J = 1.5 Hz), 7.41 (1H, d, J = 8.5 Hz), 7.40 (1H, s), 7.36 (1H, dd, J = 8.5, 1.5 Hz). 7.29 (1H, dd, J = 8.5, 1.8 Hz), 6.99 (2H, br s), 2.53 (3H, d, J = 4.3 Hz), 1.35 (9H, s),
- 171 171
- aJ o [5-amino-1-(2-met¡l-1H- bencimidazol- 5-il)- 1 Hpirazol- 4 -il] -(5- isopropil-1 H-indol-2-M)- metanona 399 1H-RMN (DMSO-D6) 8: 12.46 (1H, s), 11.56 (1H, s), 8.28 (1H, s), 7.64.7.56 (2H, br m), 7.50 (1H, s), 7.40 (1H, d, J = 8.5 Hz), 7.37 (1H, d, J = 1.5 Hz), 7.29 (1H, dd, J = 8.5, 1.8 Hz), 7.17 (1H, dd, J = 8.5, 1.5 Hz), 6.98 (2H, br s), 3.01-2.94 (1H, m), 2.53 (3H, s), 1.26 (6H, d, J = 6.7 Hz). aJ or [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1 Hpirazol-4-yl] - (5- isopropyl-1 H-indole-2-M) - methanone 399 1H-NMR (DMSO-D6) 8: 12.46 (1H, s), 11.56 (1H, s), 8.28 (1H, s), 7.64.7.56 (2H, br m), 7.50 (1H, s), 7.40 ( 1H, d, J = 8.5 Hz), 7.37 (1H, d, J = 1.5 Hz), 7.29 (1H, dd, J = 8.5, 1.8 Hz), 7.17 (1H, dd, J = 8.5, 1.5 Hz), 6.98 (2H, br s), 3.01-2.94 (1H, m), 2.53 (3H, s), 1.26 (6H, d, J = 6.7 Hz).
- 172 172
- ^oHr- vxt;- [5-am¡no-1-(2-met¡l-1H- bencimldazol- 5-II)- 1 Hpirazol-4-II] -(5- benloxi-1 H-indol-2-il)- metanona 463 1H-RMN (DMSO-D6) 8: 12.46 (1H, s), 11.58 (1H, d, J = 1.8 Hz), 8.27 (1H, d, J = 3.0 Hz), 7.65-7.55 (2H, m), 7.49-7.47 (2H, m), 7.42-7.38 (3H, m), 7.33-7.29 (3H, m), 7.21 (1H, d, J = 2.4 Hz), 7.01-6.98 (3H, m), 5.12 (2H, s), 2.53 (3H, s). ^ oHr- vxt; - [5-amine-1- (2-methyl-1H-benzimdazol-5-II) - 1 Hpyrazol-4-II] - (5- benloxy-1 H-indole-2 -il) - methanone 463 1H-NMR (DMSO-D6) 8: 12.46 (1H, s), 11.58 (1H, d, J = 1.8 Hz), 8.27 (1H, d, J = 3.0 Hz), 7.65-7.55 (2H, m), 7.49-7.47 (2H, m), 7.42-7.38 (3H, m), 7.33-7.29 (3H, m), 7.21 (1H, d, J = 2.4 Hz), 7.01-6.98 (3H , m), 5.12 (2H, s), 2.53 (3H, s).
- 173 173
- 6 ^ [5-ami no-1 -(2-met¡l-1 H- bencimidazol- 5-II)- 1 Hpirazol- 4-II] -(4- benciloxi-1 H-indol-2-il)- metanona 463 1H-RMN (DMSO-D6) 8: 12.46 (1H, s), 11.75 (1H, d, J = 1.8 Hz), 8.27 (1H, s), 7.62-7.88 (4H, m), 7.42 (2H, t, J = 10.4 Hz), 7.35-7.30 (3H, m), 7.15 (1H, dd, J = 7.9, 4.0 Hz), 7.08 (1H, d, J = 8.5 Hz), 6.97 (2H, d, J =19.5 Hz), 6.64 (1H, d, J = 7.9 Hz), 5.29 (2H, s), 2.53 (3H, s). 6 ^ [5-ami no-1 - (2-methyl-1 H- benzimidazol-5-II) - 1 Hpirazol-4-II] - (4- benzyloxy-1 H-indole-2-yl) - methanone 463 1H-NMR (DMSO-D6) 8: 12.46 (1H, s), 11.75 (1H, d, J = 1.8 Hz), 8.27 (1H, s), 7.62-7.88 (4H, m), 7.42 (2H , t, J = 10.4 Hz), 7.35-7.30 (3H, m), 7.15 (1H, dd, J = 7.9, 4.0 Hz), 7.08 (1H, d, J = 8.5 Hz), 6.97 (2H, d, J = 19.5 Hz), 6.64 (1H, d, J = 7.9 Hz), 5.29 (2H, s), 2.53 (3H, s).
- 174 174
- a H "O'-' vXXr H [5-amino-1-(2-metll-1H- bencimidazol- 5-II)- 1 Hpirazol- 4-II] -(5,6- dimetoxi-1 H-indol-2-il)- metanona 417 1H-RMN (DMSO-D6) 8: 12.45 (1H, s), 11.43 (1H, d, J = 1.6 Hz), 8.24 (1H, d, J = 4.4 Hz), 7.66-7.55 (2H, m), 7.32-7.27 (2H, m), 7.12 (1H, s), 6.94-6.91 (3H, m), 3.81 (3H, s), 3.79 (3H, s), 2.53 (3H, s). to H "O'- 'vXXr H [5-amino-1- (2-metll-1H- benzimidazol-5-II) - 1 Hpirazol-4-II] - (5,6- dimethoxy-1 H-indole- 2-yl) - methanone 417 1H-NMR (DMSO-D6) 8: 12.45 (1H, s), 11.43 (1H, d, J = 1.6 Hz), 8.24 (1H, d, J = 4.4 Hz), 7.66- 7.55 (2H, m), 7.32-7.27 (2H, m), 7.12 (1H, s), 6.94-6.91 (3H, m), 3.81 (3H, s), 3.79 (3H, s), 2.53 (3H, s).
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 175 175
- v;tc£t [5-ami no-1 -(2-metil-1 H- bencimidazol- 5-il)- 1 Hpirazol- 4-il]-(6-tert- butil-1 H-lndol-2-ll)- metanona 413 1H-RMN (DMSO-D6) 6: 12.45 (1H, s), 11.53 (1H, s), 8.28 (1H, s), 7.62-7.58 (2H, brm), 7.51 (1H, d, J = 8.5 Hz), 7.44 (1H, s), 7.38 (1H, d, J = 1.2 Hz), 7.28 (1H, dd, J = 8.5, 3.8 Hz), 7.19 (1H, dd, J = 8.5, 1.2 Hz), 6.98 (2H, br s), 2.53 (3H, s), 1.35 (9H,s). v; tc £ t [5-ami no-1 - (2-methyl-1 H- benzimidazol-5-yl) -1 Hpirazol-4-yl] - (6-tert-butyl-1 H-lndol-2- ll) - methanone 413 1H-NMR (DMSO-D6) 6: 12.45 (1H, s), 11.53 (1H, s), 8.28 (1H, s), 7.62-7.58 (2H, brm), 7.51 (1H, d , J = 8.5 Hz), 7.44 (1H, s), 7.38 (1H, d, J = 1.2 Hz), 7.28 (1H, dd, J = 8.5, 3.8 Hz), 7.19 (1H, dd, J = 8.5, 1.2 Hz), 6.98 (2H, br s), 2.53 (3H, s), 1.35 (9H, s).
- 176 176
- -íHív ff <* N O"* H [5-ami no-1 -(2-metil-1 H- bencimidazol-5-il)- 1 Hpirazol- 4-11 ]-(5-f I u o ro- 4- trifluorometil-1H- ¡ndol-2-ll)-metanona 443 1H-RMN (DMSO-D6) 6: 12.48 (1.0H, br s), 12.38 (1.0H, br s), 8.22 (1.0H, s), 7.82 (1.0H, dd, J = 9.0, 4.2 Hz), 7.64- 7.59 (2.0H, m), 7.38-7.28 (3.0H, m), 7.10-7.07 (2.OH, brm), 2.54 (3.0H, s). -íHív ff <* NO "* H [5-ami no-1 - (2-methyl-1 H- benzimidazol-5-yl) - 1 Hpirazol- 4-11] - (5-f I uo ro- 4- trifluoromethyl-1H- ndol-2-ll) -methanone 443 1H-NMR (DMSO-D6) 6: 12.48 (1.0H, br s), 12.38 (1.0H, br s), 8.22 (1.0H, s), 7.82 (1.0H, dd, J = 9.0, 4.2 Hz), 7.64-7.59 (2.0H, m), 7.38-7.28 (3.0H, m), 7.10-7.07 (2.OH, brm), 2.54 (3.0H , s).
- 177 177
- OoCHi'v «tXr [5-amino-1-(2-metil-1H- benclmldazol- 5-il)- 1 Hpirazol-4-il] -(5- fenoxi-1 H-indol-2-ll)- metanona 449 1H-RMN (DMSO-D6) 6: 12.46 (1H, s), 11.77 (1H, s), 8.27 (1H, s), 7.68-7.55 (2H, br m), 7.51 (1H, d, J = 8.8 Hz), 7.41 (1H, s), 7.37-7.33 (2H, m), 7.30- 7.27 (2H, m), 7.08 (1H, d, J = 7.5 Hz), 7.06-7.00 (2H, m), 7.03 (1H, dd, J = 8.8, 2.4 Hz), 6.96 (2H, d, J = 7.5 Hz), 2.53 (3H, s). OoCHi'v «tXr [5-amino-1- (2-methyl-1H- benclmldazol- 5-yl) - 1 Hpirazol-4-yl] - (5- phenoxy-1 H-indole-2-ll) - methanone 449 1H-NMR (DMSO-D6) 6: 12.46 (1H, s), 11.77 (1H, s), 8.27 (1H, s), 7.68-7.55 (2H, br m), 7.51 (1H, d, J = 8.8 Hz), 7.41 (1H, s), 7.37-7.33 (2H, m), 7.30-7.27 (2H, m), 7.08 (1H, d, J = 7.5 Hz), 7.06-7.00 (2H, m), 7.03 (1H, dd, J = 8.8, 2.4 Hz), 6.96 (2H, d, J = 7.5 Hz), 2.53 (3H, s).
- 178 178
- 'kX&(r. “ t Jr- [5-am¡ no-1 -(2-met¡l-1 H- bencimidazol- 5-il)- 1 Hpirazol- 4-il] -(6- metilsulfanil-1 H-indol-2- il)-metanona 403 1H-RMN (DMSO-D6) 6: 12.45 (1H, s), 11:62 (1H, d, J = 1.8 Hz), 8.29 (1H, d, J = 5.5 Hz), 7.65-7.61 (2H, m), 7.56 (1H, d, J = 8.5 Hz), 7.43 (1H, s), 7.33 (1H, s), 7.30-7.26 (1H, m), 7.02-7.00 (2H, m), 5.97 (1H, s), 2.53 (3H, d, J = 1.8 Hz), 2.52 (3H, s). 'kX & (r. "t Jr- [5-am¡ no-1 - (2-methyl-1 H- benzimidazol-5-yl) - 1 Hpirazol-4-yl] - (6- methylsulfanyl-1 H -indole-2- il) -methanone 403 1H-NMR (DMSO-D6) 6: 12.45 (1H, s), 11:62 (1H, d, J = 1.8 Hz), 8.29 (1H, d, J = 5.5 Hz), 7.65-7.61 (2H, m), 7.56 (1H, d, J = 8.5 Hz), 7.43 (1H, s), 7.33 (1H, s), 7.30-7.26 (1H, m), 7.02-7.00 (2H, m), 5.97 (1H, s), 2.53 (3H, d, J = 1.8 Hz), 2.52 (3H, s).
- 179 179
- i? oJ> tí^S [5-ami no-1 -(2-metil-1 H- bencimidazol- 5-il)- 1 Hpirazol- 4-il] -(4-tert- butil-1 H-indol-2-il)- metanona 413 1H-RMN (DMSO-D6) 6: 12.46 (1H, br s), 11.76 (1H, s), 8.19 (1H, s), 7.63- 7.58 (2H, br m). 7.42 (1H, s), 7.36 (1H, d, J = 7.9 Hz), 7.29 (1H, dd, J = 8.5, 1.8 Hz), 7.17 (1H, t, J = 7.9 Hz), 6.97 (2H, br s), 6.95 (1 H, d. J = 7.9 Hz), 2.54 (1H, s), 1.51 (9H, s). i? oJ> you ^ S [5-ami no-1 - (2-methyl-1 H- benzimidazol-5-yl) -1 Hpirazol-4-yl] - (4-tert-butyl-1 H-indole-2- il) - methanone 413 1H-NMR (DMSO-D6) 6: 12.46 (1H, br s), 11.76 (1H, s), 8.19 (1H, s), 7.63-7.58 (2H, br m). 7.42 (1H, s), 7.36 (1H, d, J = 7.9 Hz), 7.29 (1H, dd, J = 8.5, 1.8 Hz), 7.17 (1H, t, J = 7.9 Hz), 6.97 (2H, br s), 6.95 (1 H, d. J = 7.9 Hz), 2.54 (1H, s), 1.51 (9H, s).
- 180 180
- XXX? > X [5-am¡no-1-(2-metil-1H- benclmidazol- 5-il)- 1 Hpirazol- 4-il] -(5-metil- 1 H-indol-2-il)-metanona 371 1H-RMN (DMSO-D6) 6: 12.46 (1H, br s), 11.55 (1H, s), 8.27 (1H, s), 7.60- 7.58 (2H, m), 7.45 (1 H, s), 7.36 (1H, d, J = 8.4 Hz), 7.33 (1H, s), 7.27 (1H, dd, J = 8.4, 2.0 Hz), 7.07 (1H, dd, J = 8.3, 1.5 Hz), 6.96 (2H, br s), 2.52 (3H, s), 2.38 (3H, s). XXX? > X [5-amine-1- (2-methyl-1H-benclmidazol-5-yl) -1 Hpirazol-4-yl] - (5-methyl- 1 H-indole-2-yl) -methanone 371 1 H-NMR (DMSO-D6) 6: 12.46 (1H, br s), 11.55 (1H, s), 8.27 (1H, s), 7.60- 7.58 (2H, m), 7.45 (1 H, s), 7.36 (1H, d, J = 8.4 Hz), 7.33 (1H, s), 7.27 (1H, dd, J = 8.4, 2.0 Hz), 7.07 (1H, dd, J = 8.3, 1.5 Hz), 6.96 (2H, br s), 2.52 (3H, s), 2.38 (3H, s).
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 181 181
- K j. fr-ar [5-amino-1-(2-metil-1 H- bencimidazol- 5-il)- 1Hpirazol- 4-il] -(5-etil- 1 H-indol- 2-il)- metanona 385 1H-RMN (DMSO-D6) 8: 12.46 (1H, s), 11.56 (1H, s), 8.27 (1H, s), 7.607.58 (2H, m), 7.47 (1H, s), 7.38 (1H, d, J = 8.5 Hz), 7.36-7.35 (1H, m), 7.28 (1H, dd, J = 8.5, 2.1 Hz), 7.11 (1H, dd, J = 8.5, 1.7 Hz), 6.96 (2H, s), 2.69-2.66 (2H, m), 2.52 (3H, s), 1.22 (3H, t, J = 7.5 Hz). K j. fr-ar [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1Hpirazol-4-yl] - (5-ethyl- 1 H-indol-2-yl) - methanone 385 1H -RMN (DMSO-D6) 8: 12.46 (1H, s), 11.56 (1H, s), 8.27 (1H, s), 7,607.58 (2H, m), 7.47 (1H, s), 7.38 (1H, d, J = 8.5 Hz), 7.36-7.35 (1H, m), 7.28 (1H, dd, J = 8.5, 2.1 Hz), 7.11 (1H, dd, J = 8.5, 1.7 Hz), 6.96 (2H, s ), 2.69-2.66 (2H, m), 2.52 (3H, s), 1.22 (3H, t, J = 7.5 Hz).
- 182 182
- H [5-amino-1-(2-metil-1 H- bencimidazol- 5-il)- 1Hpirazol- 4-il] -(5- fluoro-6- trifluorometil- 1 H-indol -2-il)- metanona 443 1H-RMN (DMSO-D6) 8: 12.48 (1.0H, br s), 12.24 (1.0H, br s), 8.31 (1.0H, s), 7.82 (1.0H, d, J = 5.9 Hz), 7.73 (1.0H, d, J = 11.2 Hz), 7.65-7.54 (3.0H, m), 7.29 (1.0H, d, J = 8.3 Hz), 7.13-7.09 (2.0H, br m), 2.54 (3.0H, s). H [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1Hpirazol-4-yl] - (5- fluoro-6- trifluoromethyl- 1 H-indole -2-yl) - methanone 443 1H-NMR (DMSO-D6) 8: 12.48 (1.0H, br s), 12.24 (1.0H, br s), 8.31 (1.0H, s), 7.82 (1.0H, d, J = 5.9 Hz), 7.73 (1.0H, d, J = 11.2 Hz), 7.65-7.54 (3.0H, m), 7.29 (1.0H, d, J = 8.3 Hz), 7.13-7.09 (2.0H, br m), 2.54 (3.0 H, s).
- 183 183
- N freír H [5-amino-1-(2-metil-1 H- bencimidazol- 4-il)- 1Hpirazol- 4-il] -(6- fluoro-5- metoxi-1H- indol-2-il) -metanona 405 1H-RMN (DMSO-D6) 8: 12.46 (1H, s), 11.64 (1H, s), 8.26 (1H, s), 7.647.57 (2H, br m), 7.38 (1H, s), 7.32 (1H, d, J =9.1 Hz), 7.28 (1H, dd, J = 8.5, 2.4 Hz), 7,23 (1H, d, J = 11.6 Hz), 6.98 (2H, br s), 3.86 (3H, s), 2.53 (3H, s). N fry H [5-amino-1- (2-methyl-1 H- benzimidazol-4-yl) -1Hpirazol-4-yl] - (6- fluoro-5- methoxy-1H-indole-2-yl) - methanone 405 1H-NMR (DMSO-D6) 8: 12.46 (1H, s), 11.64 (1H, s), 8.26 (1H, s), 7.647.57 (2H, br m), 7.38 (1H, s), 7.32 (1H, d, J = 9.1 Hz), 7.28 (1H, dd, J = 8.5, 2.4 Hz), 7.23 (1H, d, J = 11.6 Hz), 6.98 (2H, br s), 3.86 ( 3H, s), 2.53 (3H, s).
- 184 184
- freír M [5-amino-1-(2-metil-1 H- bencimidazol-5-il)- 1Hpirazol- 4-il] -(6- cloro-5- metoxi-1H- indol-2-il) -metanona 421,423 1H-RMN (DMSO-D6) 8: 12.46 (1H, s), 11.65 (1H, s), 8.28 (1H, s), 7.657.55 (2H, br m), 7.51 (1H, s), 7.38 (1H, s), 7.31 (1H, s), 7.28 (1H, dd, J = 8.5. 2.4 Hz), 7.01 (2H, br s), 3.87 (3H, s), 2.53 (3H, s). frying M [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1Hpirazol-4-yl] - (6- chloro-5- methoxy-1H- indole-2-yl) -methanone 421,423 1H-NMR (DMSO-D6) 8: 12.46 (1H, s), 11.65 (1H, s), 8.28 (1H, s), 7.657.55 (2H, br m), 7.51 (1H, s), 7.38 (1H, s), 7.31 (1H, s), 7.28 (1H, dd, J = 8.5. 2.4 Hz), 7.01 (2H, br s), 3.87 (3H, s), 2.53 (3H, s).
- 185 185
- h * H [5-amino-1-(2-metil-1 H- bencimidazol-5-il)- 1Hpirazol- 4-il] -(5- cloro-6- metoxi-1H- indol-2-il) -metanona 421, 423 1H-RMN (DMSO-D6) 8: 12.45 (1H, s), 11.70 (1H, s), 8.25 (1H, s), 7.73 (1H, s), 7.64-7.55 (2H, br m), 7.38 (1H, s), 7.28 (1H, dd, J = 8.5, 2.4 Hz), 7.06 (1H, s), 6.97 (2H, br s), 3.89 (3H, s), 2.53 (3H, s). h * H [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1Hpirazol-4-yl] - (5- chloro-6- methoxy-1H- indole-2-yl) - methanone 421, 423 1H-NMR (DMSO-D6) 8: 12.45 (1H, s), 11.70 (1H, s), 8.25 (1H, s), 7.73 (1H, s), 7.64-7.55 (2H, br m ), 7.38 (1H, s), 7.28 (1H, dd, J = 8.5, 2.4 Hz), 7.06 (1H, s), 6.97 (2H, br s), 3.89 (3H, s), 2.53 (3H, s ).
- 186 186
- V * „ H [5-amino-1-(2-metil-1 H- bencimidazol-4-il)- 1Hpirazol- 4-il] -(6- isopropoxi- 1 H-indol-2- il)-metanona 415 1H-RMN (DMSO-D6) 8: 12.43 (1.0H, s), 11.41 (2.0H, s), 8.27 (1.0H, s), 7.7-7.50 (3.0H, m), 7.38 (1.0H, s), 7.29 (1.0H, dd, J = 8.5, 1.7 Hz), 6.956.90 (2.0H, m), 6.72 (1.0H, dd, J = 8.7, 22 Hz), 4.62-4.56 (1.0H, m), 2.53 (3.0H, s), 1.31 (6.0H, d, J = 6.1 Hz). V * „H [5-amino-1- (2-methyl-1 H- benzimidazol-4-yl) - 1 Hpirazol-4-yl] - (6- isopropoxy-1 H-indole-2- yl) -methanone 415 1 H-NMR (DMSO-D6) 8: 12.43 (1.0H, s), 11.41 (2.0H, s), 8.27 (1.0H, s), 7.7-7.50 (3.0H, m), 7.38 (1.0H, s ), 7.29 (1.0H, dd, J = 8.5, 1.7 Hz), 6.956.90 (2.0H, m), 6.72 (1.0H, dd, J = 8.7, 22 Hz), 4.62-4.56 (1.0H, m ), 2.53 (3.0H, s), 1.31 (6.0H, d, J = 6.1 Hz).
- 187 187
- *<xr [5-amino-1-(2-metil-1 H- bencimidazol- 5-il)- 1Hpirazol- 4-il] -(6- benciloxi-1 H-indol-2-il)- metanona 463 1H-RMN (DMSO-D6) 8: 12.45 (1H, s), 11.52 (1H, s), 8.27 (1H, d. J = 4.9 Hz), 7.64 (1H, dd, J 4.9, 3.3 Hz), 7.57 (2H, dd, J = 8.5, 4.3 Hz), 7.507.49 (2H, ml, 7.42-7.39 (3H, m), 7.35-7.26 (2H, m), 7.00-6.94 (3H, m), 6.82 (1H, dd, J = 8.8, 2.2 Hz), 5.14 (2H, s), 2.53 (3H, s). * <xr [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1Hpirazol-4-yl] - (6- benzyloxy-1 H-indol-2-yl) - methanone 463 1H -RMN (DMSO-D6) 8: 12.45 (1H, s), 11.52 (1H, s), 8.27 (1H, d. J = 4.9 Hz), 7.64 (1H, dd, J 4.9, 3.3 Hz), 7.57 ( 2H, dd, J = 8.5, 4.3 Hz), 7,507.49 (2H, ml, 7.42-7.39 (3H, m), 7.35-7.26 (2H, m), 7.00-6.94 (3H, m), 6.82 (1H , dd, J = 8.8, 2.2 Hz), 5.14 (2H, s), 2.53 (3H, s).
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 188 188
- prVL^i -r0 v'-ar [5-amino-1-(2-metil-1H- bencimidazol- 5-il)- 1Hpirazol- 4-il] -(4- isopropoxi-1 H-indol-2-il)- metanona 415 1H-RMN (DMSO-D6) 8: 12.47 (1.0H, br s), 11.69 (1.0H, br s), 8.23 (1.0H, s), 7.64-7.59 (2.0H, m), 7.29 (1.0H, dd, J = 8.3. 1.5 Hz), 7.25-7.25 (1.0H, br m), 7.15 (1.0H, dd, J = 8.0, 8.0 Hz), 7.04-6.97 (3.0H, m), 6.55 (1.0H, d, J = 8.4 Hz), 4.79-4.73 (1.0H, ml, 2.53 (3.0H, s), 1.38 (8.0H, d, J = 5.9 Hz). prVL ^ i -r0 v'-ar [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) - 1-Hpyrazol-4-yl] - (4- isopropoxy-1 H-indole-2-yl ) - methanone 415 1H-NMR (DMSO-D6) 8: 12.47 (1.0H, br s), 11.69 (1.0H, br s), 8.23 (1.0H, s), 7.64-7.59 (2.0H, m), 7.29 (1.0H, dd, J = 8.3. 1.5 Hz), 7.25-7.25 (1.0H, br m), 7.15 (1.0H, dd, J = 8.0, 8.0 Hz), 7.04-6.97 (3.0H, m) , 6.55 (1.0H, d, J = 8.4 Hz), 4.79-4.73 (1.0H, ml, 2.53 (3.0H, s), 1.38 (8.0H, d, J = 5.9 Hz).
- 189 189
- ^"Cír M [5-amino-1-(2-metil-1H- bencimidazol- 5-il)- 1IIpirazol- 4-il] -(2,3-dihidro- 6H-[1,4]dioxino[2,3-f] indol- 7-il)-metanona 415 1H-RMN (DMSO-D6) 8: 12.44 (1H, s), 11.27 (1H, d, J = 1.6 Hz), 8.24 (1H, s), 7.64-7.62 (1H, br m), 7.687.54 (1H, br m), 7.30-7.26 (1H, br m), 7.28 (1H, d, J = 1.6 Hz), 7.08 (1H, s), 6.97 (1H, br s), 6.91 (1H, br s), 6.87 (1H, s), 4.27-4.22 (4H, m), 2.53 (3H, s). ^ "Circle M [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1-pyrazol-4-yl] - (2,3-dihydro-6 H- [1,4] dioxin [2, 3-f] indole-7-yl) -methanone 415 1H-NMR (DMSO-D6) 8: 12.44 (1H, s), 11.27 (1H, d, J = 1.6 Hz), 8.24 (1H, s), 7.64 -7.62 (1H, br m), 7,687.54 (1H, br m), 7.30-7.26 (1H, br m), 7.28 (1H, d, J = 1.6 Hz), 7.08 (1H, s), 6.97 ( 1H, br s), 6.91 (1H, br s), 6.87 (1H, s), 4.27-4.22 (4H, m), 2.53 (3H, s).
- 190 190
- *&f¡* H [5-amino-1-(2-metil-1H- bencimidazol-5-il)- 1Hpirazol- 4-il] -(4,6-di- tertbutil- 1 H-indol-2-il)- metanona 469 1H-RMN (DMSO-D6) 8: 12.47(1.0H, br s), 11.61 (1.0H, br s), 8.19 (1.0H, s), 7.62 (2.0H, br s), 7.37 (1.0H, s), 7.32-7.28 (2.0H, m), 7.05 (1.0H, s), 6.96 (2.0H, br s), 2.53 (3.0H, s), 1.51 (9.0H, s), 1.34 (9.0H, s). * & f¡ * H [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) - 1 Hpirazol-4-yl] - (4,6-di-tertbutyl- 1 H-indol-2-yl ) - methanone 469 1H-NMR (DMSO-D6) 8: 12.47 (1.0H, br s), 11.61 (1.0H, br s), 8.19 (1.0H, s), 7.62 (2.0H, br s), 7.37 (1.0H, s), 7.32-7.28 (2.0H, m), 7.05 (1.0H, s), 6.96 (2.0H, br s), 2.53 (3.0H, s), 1.51 (9.0H, s), 1.34 (9.0H, s).
- 191 191
- P 2-[5-amino-1-(2-metil- 1H- bencimidazol-5-il)- 1Hpirazol- 4-carbonil]- 1 Hindol- 4-carbonitrilo 382 1H-RMN (DMSO-D6) 8; 12.44 (1.0H, s), 12.33 (1.0H, s), 8.36 (1.0H, s), 7.84 (1.0H, d, J = 8.2 Hz), 7.70-7.60 (3.0H, m), 7.45-7.35 (2.0H, m), 7.29 (1.0H, dd, J = 8.5, 1.9 Hz), 7.06 (1.0H, m), 2.53 (3.0H, s). P 2- [5-Amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1Hpyrazol-4-carbonyl] -1 Hindol-4-carbonitrile 382 1 H-NMR (DMSO-D6) 8; 12.44 (1.0H, s), 12.33 (1.0H, s), 8.36 (1.0H, s), 7.84 (1.0H, d, J = 8.2 Hz), 7.70-7.60 (3.0H, m), 7.45-7.35 (2.0H, m), 7.29 (1.0H, dd, J = 8.5, 1.9 Hz), 7.06 (1.0H, m), 2.53 (3.0H, s).
- 192 192
- \. .n . jlJL^í nh <3 cWv [5-amino-1-(2-metil-1H- bencimidazol- 5-il)- 111pirazol- 4-il] -(5-imidazol- 1-il-1H-indol-2-il)-metanona 423 1H-RMN (DMSO-D6) 8: 8.31 (1H, s), 8.17 (1H, s), 7.86 (1H, d, J = 2.0 Hz), 7.70 (1H, s), 7.60-7.59 (3H, m), 7.50-7.47 (2H, m), 7.27 (1H, dd, J = 8.6 2.0 Hz), 7.11 (1H, d, J 0.8 Hz), Hzl, 7.09 (2H, br s ), 2.53 (3H, s). \. .n. jlJL ^ í nh <3 cWv [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) - 111pyrazol-4-yl] - (5-imidazol-1-yl-1H-indole-2- il) -methanone 423 1H-NMR (DMSO-D6) 8: 8.31 (1H, s), 8.17 (1H, s), 7.86 (1H, d, J = 2.0 Hz), 7.70 (1H, s), 7.60- 7.59 (3H, m), 7.50-7.47 (2H, m), 7.27 (1H, dd, J = 8.6 2.0 Hz), 7.11 (1H, d, J 0.8 Hz), Hzl, 7.09 (2H, br s), 2.53 (3H, s).
- 193 193
- -!■> ^-ar [5-amino-1-(2-metil-1H- bencimidazol-5-il)- 1Hpirazol- 4-il] -(5- trifluorometilsulfanil-1 H- indol -2-il)-metanona 467 1H-RMN (DMSO-D6) 8: 12.31 (1H, br s], 8.32 (1H, s), 8.09 (1H, s), 7.62 (1H, d. J = 2.0 Hz], 7.61-7.69 (2H, m), 7.64 (1H, s), 7.48 (1H, d, J = 8.4 Hz), 7.28 (1H, dd, J = 8.6, 2.0 Hz), 7.14 (2H, brv s), 2.53 (3H, s). -! ■> ^ -ar [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) - 1 Hpyrazol-4-yl] - (5- trifluoromethylsulfanyl-1 H- indole -2-yl) - methanone 467 1H-NMR (DMSO-D6) 8: 12.31 (1H, br s], 8.32 (1H, s), 8.09 (1H, s), 7.62 (1H, d. J = 2.0 Hz], 7.61-7.69 ( 2H, m), 7.64 (1H, s), 7.48 (1H, d, J = 8.4 Hz), 7.28 (1H, dd, J = 8.6, 2.0 Hz), 7.14 (2H, brv s), 2.53 (3H, s).
- 194 194
- íi ^ Cxxv [5-amino-1-(2 -metil-1H- bencimidazol-5-il)-1 IIpi razol- 4-il] -(5- metilsulfanil-1 H- indol-2-il)-metanona 403 1H-RMN (DMSO-D6) 8: 12.48 (1H, s), 11.76 (1H, s), 8.29 (1H, s), 7.627.62 (3H, m), 7.44 (1H, d, J = 8.6 Hz), 7.39 (1H, s), 7.29 (1H, dd, J = 8.6, 2.0 Hz), 7.23 (1H, dd, J = 8.6, 1.8 Hz), 7.02 (2H, br s), 3.34 (3H, s), 2.54 (3H, s). í ^ Cxxv [5-amino-1- (2-methyl-1 H- benzimidazol-5-yl) -1 IIpi razol-4-yl] - (5- methylsulfanyl-1 H- indole-2-yl) -methanone 403 1H-NMR (DMSO-D6) 8: 12.48 (1H, s), 11.76 (1H, s), 8.29 (1H, s), 7.627.62 (3H, m), 7.44 (1H, d, J = 8.6 Hz ), 7.39 (1H, s), 7.29 (1H, dd, J = 8.6, 2.0 Hz), 7.23 (1H, dd, J = 8.6, 1.8 Hz), 7.02 (2H, br s), 3.34 (3H, s ), 2.54 (3H, s).
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 195 195
- H ^ h L í ^ [5-amino-1-(2-metil-1H- bencimidazol-5-il)- 1 Hpirazol-4-il] -(5- metanosulfonilo-1 H-indol- 2-il)-metanona 435 1H-RMN (DMSO-D6) 8: 12.46 (1H, br s), 12.30 (1H, b, s), 8.34-8.30 (1H, m), 8.33 (1H, s). 7.76 (1H, dd, J = 8.6. 1.8 Hz). 7.72-7.68 (2H, m), 7.6 8-7.65 (1H, m), 7- 62-7.60 (1H, m), 7.29 (1H, dd. J = 8.6, 2.0 Hz), 7.08 (2H, br s), 3.34 (3H, s), 2.54 (3H, s). H ^ h L í ^ [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) - 1 Hpirazol-4-yl] - (5- methanesulfonyl-1 H-indole-2-yl) - methanone 435 1 H-NMR (DMSO-D6) 8: 12.46 (1H, br s), 12.30 (1H, b, s), 8.34-8.30 (1H, m), 8.33 (1H, s). 7.76 (1H, dd, J = 8.6. 1.8 Hz). 7.72-7.68 (2H, m), 7.6 8-7.65 (1H, m), 7- 62-7.60 (1H, m), 7.29 (1H, dd. J = 8.6, 2.0 Hz), 7.08 (2H, br s ), 3.34 (3H, s), 2.54 (3H, s).
- 247 247
- [5-amino-1-(2-metil-1H- bencimidazol-5-il)- 1Hpirazol- 4-il]- benzofurano- 2-il- metanona 358 9.21 (m, 1H), 8.52 (s, 1H), 7.73 (d, J= 7.8 Hz, 1H), 7.64 (d, J= 8.4 Hz, 1H), 7.61 (s, 1H), 7.47 (t, J= 8Hz, 1H), 7.40 (m, 1H), 7.32 (t, J= 7.6 Hz, 1H), 6.17 (m, 2H), 2.66 (s, 3H) [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpirazol-4-yl] -benzofuran-2-yl-methanone 358 9.21 (m, 1H), 8.52 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.61 (s, 1H), 7.47 (t, J = 8Hz, 1H), 7.40 (m, 1H), 7.32 (t, J = 7.6 Hz, 1H), 6.17 (m, 2H), 2.66 (s, 3H)
- 248 248
- 0 [5-amino-1-(2-metil-1H- bencimidazol-5-il)- 1 Hpirazol- 4-il]-benzo[b] tiofen-2-il-metanona 374 12.46 (s, 1H), 8.42 (s, 1H), 8.35 (m, 1H), 8.05 (m, 2H), 7.65 (m, 1H), 7.56 (m, 1H), 7.51 (m, 2H), 7.28 (m, 1H), 7.09 (s, 1H), 7.03 (s, 1H), 2.54 (s, 3H). 0 [5-amino-1- (2-methyl-1H- benzimidazol-5-yl) -1 Hpirazol-4-yl] -benzo [b] thiophene-2-yl-methanone 374 12.46 (s, 1H), 8.42 (s, 1H), 8.35 (m, 1H), 8.05 (m, 2H), 7.65 (m, 1H), 7.56 (m, 1H), 7.51 (m, 2H), 7.28 (m, 1H), 7.09 ( s, 1H), 7.03 (s, 1H), 2.54 (s, 3H).
- 249 249
- [5-amino-1-(2-metil-1H- bencimidazol-5-il)- 1Hpirazol- 4-il]- benzotiazol- 2-il-metanona 375 8.83 (s, 1H), 8.27 (m, 2H), 7.86 (m, 2H), 7.64 (m, 2H), 7.57 (m, 1H), 7.44 (s, 2H), 2.73 (s, 3H). [5-amino-1- (2-methyl-1H- benzimidazol-5-yl) -1Hpirazol-4-yl] -benzothiazol-2-yl-methanone 375 8.83 (s, 1H), 8.27 (m, 2H), 7.86 (m, 2H), 7.64 (m, 2H), 7.57 (m, 1H), 7.44 (s, 2H), 2.73 (s, 3H).
- 250 250
- [5-amino-1-(2-metil-1H- bencimidazol- 5-il)- 1Hpirazol- 4-il]-(4- fluorofenil)- metanona 336 7.85 (m, 4H), 7.55 (d, J= 8.4 Hz, 1H), 7.36 (t, J= 8.7 Hz, 2H), 7.28 (s, 1H), 7.21 (s, 2H), 7.15 (s, 1H), 7.03 (s, 1H), 2.73 (s, 3H). [5-amino-1- (2-methyl-1H- benzimidazol-5-yl) -1Hpirazol-4-yl] - (4- fluorophenyl) -methanone 336 7.85 (m, 4H), 7.55 (d, J = 8.4 Hz, 1H), 7.36 (t, J = 8.7 Hz, 2H), 7.28 (s, 1H), 7.21 (s, 2H), 7.15 (s, 1H), 7.03 (s, 1H), 2.73 (s, 3H ).
- 251 251
- [5-amino-1-(2-metil-1H- bencimidazol-5-il)- 1Hpirazol-4-il]-(3- clorofenil)- metanona 352 7.77 (m, 1H), 7.74 (m, 1H), 7.65 (m, 1H), 7.57 (m, 3H), 7.24 (d, J= 8.6 Hz, 2H), 7.03 (br s, 2H), 2.51 (m, 3H). [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpirazol-4-yl] - (3- chlorophenyl) -methanone 352 7.77 (m, 1H), 7.74 (m, 1H), 7.65 (m, 1H), 7.57 (m, 3H), 7.24 (d, J = 8.6 Hz, 2H), 7.03 (br s, 2H), 2.51 (m, 3H).
- 252 252
- Qry^^^r-C^ [5-amino-1-(2-metil-1H- bencimidazol- 5-il)- 1Hpirazol- 4-il]-quinolin-3- il-metanona 369 9.21 (s, 1H), 8.85 (s, 1H), 8.23 (d, J= 8.1 Hz, 1H), 8.12 (d, J= 8.4 Hz, 1H), 8.06 (s, 1H), 7.91 (m, 3H), 7.73 (t, J= 6.2 Hz, 1H), 7.64 (d, J= 8.4 Hz, 1H), 7.33 (s, 2H), 2.74 (s, 3H). Qry ^^^ rC ^ [5-amino-1- (2-methyl-1H- benzimidazol- 5-yl) - 1 Hpirazol- 4-yl] -quinolin-3- il-methanone 369 9.21 (s, 1H), 8.85 (s, 1H), 8.23 (d, J = 8.1 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.06 (s, 1H), 7.91 (m, 3H), 7.73 (t, J = 6.2 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.33 (s, 2H), 2.74 (s, 3H).
- 253 253
- [5-amino-1-(2-metil-1H- bencimidazol- 5-il)- 1 Hpirazol-4-il]-quinolin-7-il- metanona 369 9.05 (m, 1H), 8.52 (d, J= 8.2 Hz, 1H), 8.38 (s, 1H), 8.17 (d, J= 8.4 Hz, 1H), 7.93 (m, 4H), 7.69 (m, 2H), 7.32 (s, 2H), 2.79 (s, 3H). [5-amino-1- (2-methyl-1H- benzimidazol-5-yl) -1 Hpirazol-4-yl] -quinolin-7-yl-methanone 369 9.05 (m, 1H), 8.52 (d, J = 8.2 Hz, 1H), 8.38 (s, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.93 (m, 4H), 7.69 (m, 2H), 7.32 (s, 2H), 2.79 (s, 3H).
- 254 254
- [5-amino-1-(2-metil-1H- bencimidazol-5-il)- 1Hpirazol- 4-il]-quinolin-6- il-metanona 369 9.02 (d, J= 5.1 Hz, 1H), 8.51 (d, J= 8.4 Hz, 1H), 8.37 (s, 1H), 8.16 (d, J= 8.3 Hz, 1H), 7.92 (m, 4H), 7.66 (m, 2H), 7.32 (m, 2H), 2.74 (s, 3H). [5-amino-1- (2-methyl-1H- benzimidazol-5-yl) -1Hpirazol-4-yl] -quinolin-6- yl-methanone 369 9.02 (d, J = 5.1 Hz, 1H), 8.51 ( d, J = 8.4 Hz, 1H), 8.37 (s, 1H), 8.16 (d, J = 8.3 Hz, 1H), 7.92 (m, 4H), 7.66 (m, 2H), 7.32 (m, 2H), 2.74 (s, 3H).
Etapa 2: Síntesis de 2-(1-bencenosulfonil-1H-indol-2-carbonil)-3-dimetilamino-acrilonitrilo (1083)Stage 2: Synthesis of 2- (1-benzenesulfonyl-1H-indole-2-carbonyl) -3-dimethylamino-acrylonitrile (1083)
Se adicionó N,N-dimetilformamida dimetilacetal (620 pl) a temperatura ambiente a una solución de tetrahidrofurano (THF) (8.5 mi) de 3-(1-bencenosulfonil-1H-indol-2-il)-3-oxo-propionitrilo (1.0 g, 3.08 mmol), y se agitó, durante diez minutos. A continuación, la mezcla de reacción se concentró bajo presión reducida para dar el 2-(1-bencenosulfonil- 5 1H-¡ndol-2- carbonil)-3-d¡met¡lamino-acrilonitrilo en bruto como un material amorfo de color amarillo. El producto enN, N-dimethylformamide dimethylacetal (620 pl) was added at room temperature to a solution of tetrahydrofuran (THF) (8.5 ml) of 3- (1-benzenesulfonyl-1H-indole-2-yl) -3-oxo-propionitrile ( 1.0 g, 3.08 mmol), and stirred, for ten minutes. Then, the reaction mixture was concentrated under reduced pressure to give the crude 2- (1-benzenesulfonyl-5-1-H -dol-2-carbonyl) -3-d-melamine-acrylonitrile as a colored amorphous material. yellow. The product in
bruto obtenido se utilizó en reacciones posteriores sin purificación.Gross obtained was used in subsequent reactions without purification.
ESI (LC-MS modo positivo) m/z 380 [(M+H)+]ESI (LC-MS positive mode) m / z 380 [(M + H) +]
Los compuestos de los números 1084 a 1184, y 1528 a 1549 enumerados en la Tabla 9, se sintetizaron mediante elThe compounds of numbers 1084 to 1184, and 1528 to 1549 listed in Table 9, were synthesized by
mismo método como en la Etapa 2.Same method as in Stage 2.
10 Tabla 910 Table 9
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1084 1084
- tp oxlTL, c t 2-(1-bencenosulfon¡l-6-morfol¡n-4-¡lmetil-1H-¡ndol-2-carbon¡l)- 3-d¡met¡lam¡no-acr¡lonitrilo 479 tp oxlTL, c t 2- (1-benzenesulfon¡l-6-morphol-4-¡methyl-1H-¡ndol-2-carbon¡l) - 3-d¡met¡lam¡no-acrlonitrile 479
- 1085 1085
- p °*ío o 2-(1-bencenosulfonil-5-morfolin-4-ilmet¡l-1H-indol-2-carbonil)- 3-dimet¡lamino-acr¡lonitrilo 479 p ° * io or 2- (1-benzenesulfonyl-5-morpholin-4-ylmethyl-1H-indole-2-carbonyl) - 3-dimethylamino-acrylonitrile 479
- 1086 1086
- >9 0 £ 2-(1-bencenosulfon¡l-4-morfolin-4-¡l-1H-indol-2-carbonil)-3- dlmetllamino-acrilonitrilo 465 > 9 0 £ 2- (1-benzenesulfon¡l-4-morpholin-4-l-1H-indole-2-carbonyl) -3- dlmethylamino-acrylonitrile 465
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1087 1087
- Q 2-(1-bencenosulfonil-4-morfolin-4-ilmetil-1H-indol-2-carbonil)- 3-dimetilamino-acrilonitrilo 479 Q 2- (1-Benzenesulfonyl-4-morpholin-4-ylmethyl-1H-indole-2-carbonyl) - 3-dimethylamino-acrylonitrile 479
- 1088 1088
- .9. 0-!l=5j¡ tert-butil éster del ácido 4-[1-bencenosulfonil-2-(2-ciano-3- dimetilamino-acriloil)-1H-indol-5-ilmetil]-piperazina-1- carboxílico 578 .9. 0-! L = 5j-tert-butyl ester of 4- [1-benzenesulfonyl-2- (2-cyano-3- dimethylamino-acryloyl) -1H-indole-5-ylmethyl] -piperazine-1-carboxylic acid 578
- 1089 1089
- ■S 2-(1-bencenosulfonil-4-fluoro-1H-indol-2-carbonil)-3- dimetilamino-acrilonitrilo 398 ■ S 2- (1-Benzenesulfonyl-4-fluoro-1H-indole-2-carbonyl) -3-dimethylamino-acrylonitrile 398
- 1090 1090
- O ,xxK. 2-(1-bencenosulfonil-5-fluoro-1H-indol-2-carbonil)-3- dimetilamino-acrilonitrilo 398 Or, xxK. 2- (1-Benzenesulfonyl-5-fluoro-1H-indole-2-carbonyl) -3-dimethylamino-acrylonitrile 398
- 1091 1091
- ■Q 'xSk l 2-(1-bencenosulfonil-6-fluoro-1H-indol-2-carbonil)-3- dimetilamino-acrilonitrilo 398 ■ Q 'xSk l 2- (1-benzenesulfonyl-6-fluoro-1H-indole-2-carbonyl) -3- dimethylamino-acrylonitrile 398
- 1092 1092
- •P / 2-(1-bencenosulfonil-1H-pirrolo[2,3-b] piridina-2-carbonil)-3- dimetilamino -acrilonitrilo 381 • P / 2- (1-Benzenesulfonyl-1H-pyrrolo [2,3-b] pyridine-2-carbonyl) -3- dimethylamino-acrylonitrile 381
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1093 1093
- •P 0 / 2-(1-bencenosulfonil-1H-pirrolo[3,2-c] piridina-2- carbonil)-3-dimetilamino -acrilonitrilo 381 • P 0 / 2- (1-benzenesulfonyl-1H-pyrrolo [3,2-c] pyridine-2-carbonyl) -3-dimethylamino-acrylonitrile 381
- 1094 1094
- 0 l' 2-(1-bencenosulfonil-5-floro-6-morfolm-4-ilmetil-1H- indol-2-carbonil)-3-dimetilaminoacrilonitrilo 497 0 1 '2- (1-benzenesulfonyl-5-floro-6-morpholm-4-ylmethyl-1H- indole-2-carbonyl) -3-dimethylaminoacrylonitrile 497
- 1095 1095
- Q oO^OÍp, Pl— f 2-[1-bencenosulfonil-6-(2-morfolin-4-il -etoxi)-1H-indol- 2-carbonil]-3-dimetilammoacrilonitrilo 509 Q oO ^ OIP, Pl— f 2- [1-benzenesulfonyl-6- (2-morpholin-4-yl-ethoxy) -1H-indole-2-carbonyl] -3-dimethylammoacrylonitrile 509
- 1096 1096
- Q °-síE H— r 2-[1-bencenosulfonil-6-(tetrahidro-piran -4-iloxi)-1H- indol-2-carbonil]-3-dimetilaminoacrilonitrilo 480 Q ° -sí H— r 2- [1-benzenesulfonyl-6- (tetrahydro-pyran -4-yloxy) -1H- indole-2-carbonyl] -3-dimethylaminoacrylonitrile 480
- 1097 1097
- Q-=J fJTj 51 V 2-[4-cloro-1-(tolueno-4-sulfonil)-1H-indol-2-carboml]-3- dimetilamino-acrilonitrilo 428, 430 Q- = J fJTj 51 V 2- [4-chloro-1- (toluene-4-sulfonyl) -1H-indole-2-carboml] -3- dimethylamino-acrylonitrile 428, 430
- 1098 1098
- <¡> "*f*Q Or^ t 3-dimetilamino-2-[3-fluoro-1-(tolueno -4- sulfonil)-1H- indol-2-carbonil] -acrilonitrilo 412 <¡> "* F * Q Or ^ t 3-dimethylamino-2- [3-fluoro-1- (toluene -4-sulfonyl) -1H- indole-2-carbonyl] -acrylonitrile 412
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1099 1099
- í f ^ y* * 3-dimetilamino-2-[5-(1-metil-piperidin -4-il)-1-(tolueno-4- sulfonil)-1 H-indol -2-carbonil]-acrilonitrilo 491 í f ^ y * * 3-dimethylamino-2- [5- (1-methyl-piperidin -4-yl) -1- (toluene-4- sulfonyl) -1 H-indole -2-carbonyl] -acrylonitrile 491
- 1100 1100
- & °'Sc YV^ y tert-butil éster del ácido 4-[2-(2-ciano-3-dimetilamino- acriloil)-1 -(tolueno-4-sulfonil)-1 H-indol-5-il] -3,6-dihidro-2H- piridina-1-carboxílico 575 & ° 'Sc YV ^ and 4- [2- (2-Cyano-3-dimethylamino-acryloyl) -1 - (toluene-4-sulfonyl) -1 H-indole-5-yl] - tert-butyl ester 3,6-dihydro-2H-pyridine-1-carboxylic 575
- 1101 1101
- i >°YfJ V 1 ü ' tert-butil éster del ácido 4-[2-(2-ciano-3-dimetilamino- acriloil) -1-(tolueno-4-sulfonil)-1H-indol-5-il]-piperidina-1- carboxílico 577 i> ° YfJ V 1 ü 'tert-butyl acid ester 4- [2- (2-cyano-3-dimethylamino-acryloyl) -1- (toluene-4-sulfonyl) -1H-indole-5-yl] - piperidine-1- carboxylic 577
- 1102 1102
- í ó y1 3-dimetilamino-2-[5-((R)-3-fluoro-pirrolidin-1-ilmetil)-1- (tolueno-4-sulfonil)-1 H-indol-2-carbonil] -acrilonitrilo 495 í y y1 3-dimethylamino-2- [5 - ((R) -3-fluoro-pyrrolidin-1-ylmethyl) -1- (toluene-4-sulfonyl) -1 H-indole-2-carbonyl] -acrylonitrile 495
- 1103 1103
- 1 0 ' tert-butil éster del ácido 4-[2-(2-ciano-3-dimetilamino- acriloil) -6-fluoro-1-(tolueno-4-sulfonil)-1 H-indol-5-il]- piperidina-1-carboxílico 595 1 0 '4- [2- (2-Cyano-3-dimethylamino-acryloyl) -6-fluoro-1- (toluene-4-sulfonyl) -1 H-indole-5-yl] - tert-butyl ester piperidine-1-carboxylic 595
- 1104 1104
- ó °So o°H- ' ^ N- r 3-dimetilamino-2-[6-fluoro-5-(1-metil -piperidin-4-il)-1- (tolueno-4-sulfonil) -1 H-indol- 2-carbonil]-acrilonitrilo 509 or ° So or ° H- '^ N- r 3-dimethylamino-2- [6-fluoro-5- (1-methyl -piperidin-4-yl) -1- (toluene-4-sulfonyl) -1 H- indole-2-carbonyl] -acrylonitrile 509
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1105 1105
- Ví- f 2-[1-bencenosulfon¡l-6-(tert-but¡ld¡fen¡l - silaniloximetil)-1 H-indol-2-carbonil] -3-dimetilamino- acrilonitrilo 648 Víf 2- [1-benzenesulfon¡l-6- (tert-but¡ld¡fen¡l - silaniloxymethyl) -1 H-indole-2-carbonyl] -3-dimethylamino-acrylonitrile 648
- 1106 1106
- 3-dimetilamino-2-[5-( 1 -isopropil-p¡per¡din-4-il)-1 - (tolueno-4-sulfonil) -1 H-indol-2-carbonil]-acrilonitrilo 519 3-dimethylamino-2- [5- (1-isopropyl-p¡per¡din-4-yl) -1 - (toluene-4-sulfonyl) -1 H-indole-2-carbonyl] -acrylonitrile 519
- 1107 1107
- 0Ó Vv*°° W - 3-dimetilami no-2-[6-fl uoro-5-(1 -isopropilpiperidin-4-il)- 1 -(tolueno-4-sulfonil)-1 H-indol-2-carbonil] -acrilonitrilo 537 0Ó Vv * °° W - 3-dimethylami no-2- [6-fl uoro-5- (1-isopropylpiperidin-4-yl) - 1 - (toluene-4-sulfonyl) -1 H-indole-2-carbonyl ] -acrylonitrile 537
- 1108 1108
- \ o i __f -3s~o Jm 2-(1-bencenosulfon¡l-6-[2-(4-metilpiperidin-1-il)-etoxi]- 1 H-indol -2-carbon¡l)-3-d¡metilamino-acrilonitrilo 522 \ o __f -3s ~ or Jm 2- (1-benzenesulfon¡l-6- [2- (4-methylpiperidin-1-yl) -ethoxy] - 1 H-indole -2-carbon¡l) -3-d Methylamino-acrylonitrile 522
- 1109 1109
- H- t 3-d¡met¡lamino-2-[6-fluoro-5-(4-met¡lp¡peraz¡n-1- ilmetil) -1-(tolueno -4-sulfonil)-1 H-indol-2-carbonil]- acrilonitrilo 524 H- t 3-d¡met¡lamino-2- [6-fluoro-5- (4-methyl-peraz-1-ylmethyl) -1- (toluene -4-sulfonyl) -1 H-indole -2-carbonyl] - acrylonitrile 524
- 1110 1110
- A p N- / 3-dimet¡lamino-2-[6-fluoro-5-p¡rrol¡d¡n -1 -ilmetil-1 - (tolueno-4-sulfonil)-1 H-indol-2-carbonil]-acrilonitrilo 495 A p N- / 3-dimethylamino-2- [6-fluoro-5-prolrol-1-ylmethyl-1 - (toluene-4-sulfonyl) -1 H-indole-2-carbonyl ] -acrylonitrile 495
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1111 1111
- Ó °sc N t 3-dimetilamino-2-[6-(1-metil-piperidin -4-il)-1-(tolueno-4- sulfonil)-1 H-indol -2-carbonil]-acrilonitrilo 491 Ó ° sc N t 3-dimethylamino-2- [6- (1-methyl-piperidin -4-yl) -1- (toluene-4- sulfonyl) -1 H-indole -2-carbonyl] -acrylonitrile 491
- 1112 1112
- crCC^T“ 2-[5-(1-ciclopentil-piperidi n-4-il)-1-(tol ueno-4-sulfonil)- 1H-indol-2-carbonil]-3-dimetilaminoacrilonitrilo 545 crCC ^ T “2- [5- (1-cyclopentyl-piperidi n-4-yl) -1- (toluene-4-sulfonyl) -1H-indole-2-carbonyl] -3-dimethylaminoacrylonitrile 545
- 1113 1113
- í. a" > 2-[5-(1-ciclohexil-piperidin-4-il)-1-(tolueno-4-sulfonil)- 1H-indol-2-carbonil]-3-dimetilaminoacrilonitrilo 559 í. a "> 2- [5- (1-Cyclohexyl-piperidin-4-yl) -1- (toluene-4-sulfonyl) -1H-indole-2-carbonyl] -3-dimethylaminoacrylonitrile 559
- 1114 1114
- *=j=® a. P\? 1 2-[4-bromo-1-(tolueno-4-sulfonil)-1H-pirrol-2-carbonil]- 3-dimetilamino-acrilonitrilo 422, 424 * = j = ® a. P \? 1 2- [4-Bromo-1- (toluene-4-sulfonyl) -1H-pyrrole-2-carbonyl] - 3-dimethylamino-acrylonitrile 422, 424
- 1115 1115
- 0 1 3-dimetilamino-2-[1-(tolueno-4-sulfonil)-1Hpirrol-2- carbonil]-acrilonitrilo 344 0 1 3-dimethylamino-2- [1- (toluene-4-sulfonyl) -1Hpyrrol-2- carbonyl] -acrylonitrile 344
- 1116 1116
- eJ — / 2-(6-benciloxi-1 H-indol-2-carbonil) -3-dimetilamino- acrilonitrilo 346 eJ - / 2- (6-benzyloxy-1 H-indol-2-carbonyl) -3-dimethylamino-acrylonitrile 346
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1117 1117
- TJ— / 3-dimetilamino-2-(5-metoxi-1H-indol-2-carbonil)- acrilonitrilo 270 TJ— / 3-dimethylamino-2- (5-methoxy-1H-indole-2-carbonyl) - acrylonitrile 270
- 1118 1118
- ft- lr 2-[6-butil-1-(tolueno-4-sulfonil)-1H-indol-2-carbonil]-3- dimetilamino-acrilonitrilo 450 ft- lr 2- [6-butyl-1- (toluene-4-sulfonyl) -1H-indole-2-carbonyl] -3- dimethylamino-acrylonitrile 450
- 1119 1119
- ó °-s=on Y 3- dimetilamino-2-[5-(1-isopropryl-piperidin-4-il)-1-(tolueno- 4- sulfonil)-6-trifluorometil-1 H-indol-2-carbonil] -acrilonitrilo 587 or ° -s = on Y 3- dimethylamino-2- [5- (1-isopropyl-piperidin-4-yl) -1- (toluene-4-sulfonyl) -6-trifluoromethyl-1 H-indole-2-carbonyl ] -acrylonitrile 587
- 1120 1120
- '■ N — 2-(4,6-dimetoxi-1 H-indol-2-carbonil) -3-dimetilamino- acrilonitrilo 300 '■ N - 2- (4,6-dimethoxy-1 H-indol-2-carbonyl) -3-dimethylamino-acrylonitrile 300
- 1121 1121
- H * ^j^yp X i ' N— / 3-dimetilamino-2-(4-metoxi-1H-indol-2-carbonil)- acrilonitrilo 270 H * ^ j ^ yp X i 'N— / 3-dimethylamino-2- (4-methoxy-1H-indole-2-carbonyl) - acrylonitrile 270
- 1122 1122
- r 3-dimetilamino-2-(6-metoxi-1H-indol-2-carbonil)- acrilonitrilo 270 r 3-dimethylamino-2- (6-methoxy-1H-indole-2-carbonyl) - acrylonitrile 270
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1123 1123
- H N- / 3-dimetilamino-2-(4,6-dimetiMH-mdol-2-carbonil)- acrilonitrilo 268 H N- / 3-dimethylamino-2- (4,6-dimetiMH-mdol-2-carbonyl) - acrylonitrile 268
- 1124 1124
- $ i 2-[6-bromo-1-(tolueno-4-sulfonil)-1H-indol-2-carbonil]-3- dimetilamino-acrilonitrilo 472, 474 2- [6-Bromo-1- (toluene-4-sulfonyl) -1H-indole-2-carbonyl] -3-dimethylamino-acrylonitrile 472, 474
- 1125 1125
- Ó 2-[6-ciclopropil-1-(tolueno-4-sulfonil) -1 H-indol-2- carbonil]-3-dimetilamino -acrilonitrilo 434 OR 2- [6-Cyclopropyl-1- (toluene-4-sulfonyl) -1 H-indole-2-carbonyl] -3-dimethylamino-acrylonitrile 434
- 1126 1126
- 1 il. 2-(5-tert-butil-1 H-indol-2-carbonil) -3-dimetilamino- acrilonitrilo 296 1 il. 2- (5-tert-butyl-1 H-indol-2-carbonyl) -3-dimethylamino-acrylonitrile 296
- 1127 1127
- H N- / 3-dimetilamino-2-(5-isopropil-1H-indol-2-carbonil)- acrilonitrilo 282 H N- / 3-dimethylamino-2- (5-isopropyl-1H-indole-2-carbonyl) - acrylonitrile 282
- 1128 1128
- Í-OVC, tí— í 2-(5-benciloxi-1 H-indol-2-carbonil) -3-dimetilamino- acrilonitrilo 346 Í-OVC, ti 2- 2- (5-benzyloxy-1 H-indol-2-carbonyl) -3-dimethylamino-acrylonitrile 346
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1129 1129
- H * ó 2-(4-benciloxi-1 H-indol-2-carbonil) -3-dimetilamino- acrilonitrilo 346 H * or 2- (4-benzyloxy-1 H-indol-2-carbonyl) -3-dimethylamino-acrylonitrile 346
- 1130 1130
- J jT -fr M — r 2-[5-bromo-1-(tolueno-4-sulfonil)-1H-indol-2-carbonil]-3- dimetilamino-acrilonitrilo 472, 474 J jT -fr M-r 2- [5-bromo-1- (toluene-4-sulfonyl) -1H-indole-2-carbonyl] -3- dimethylamino-acrylonitrile 472, 474
- 1131 1131
- -0ig5 \ \~ i 2-(5,6-dimetoxi-1 H-indol-2-carbonil) -3-dimetilamino- acrilonitrilo 300 -0ig5 \ \ ~ i 2- (5,6-dimethoxy-1 H-indol-2-carbonyl) -3-dimethylamino-acrylonitrile 300
- 1132 1132
- p. o=s=o0 0^ C I 1 2-(1-bencenosulfonil-4-yodo-1H-indol -2-carbonil)-3- dimetilamino-acrilonitrilo 506 p. o = s = o0 0 ^ C I 1 2- (1-benzenesulfonyl-4-iodo-1H-indole -2-carbonyl) -3-dimethylamino-acrylonitrile 506
- 1133 1133
- (¡3 l Ap|KNP 3-dimetilamino-2-[6-isopropil-1-(tolueno-4-sulfonil)-1H- indol-2-carbonil] —acrilonitrilo 436 (3 l Ap | KNP 3-dimethylamino-2- [6-isopropyl-1- (toluene-4-sulfonyl) -1H- indole-2-carbonyl] —acrylonitrile 436
- 1134 1134
- P ^l — 2-(1-bencenosulfonil-1H-pirrolo[3,2-b] piridina-2-carbonil)- 3-dimetilamino -acrilonitrilo 381 P ^ l - 2- (1-benzenesulfonyl-1H-pyrrolo [3,2-b] pyridine-2-carbonyl) - 3-dimethylamino-acrylonitrile 381
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1135 1135
- 0 H— i 2-[5-bromo-1-(tolueno-4-sulfonil)-6-trifluorometil-1H- indol-2-carbonil] -3-dimetilamino-acrilonitrilo 542, 542 0 H— i 2- [5-Bromo-1- (toluene-4-sulfonyl) -6-trifluoromethyl-1H- indole-2-carbonyl] -3-dimethylamino-acrylonitrile 542, 542
- 1136 1136
- F ' 2-[6-bromo-5-fluoro-1-(tolueno-4-sulfonil)-1H-indol-2- carbonil]-3-dimetilamino-acrilonitrilo 490, 492 F '2- [6-Bromo-5-fluoro-1- (toluene-4-sulfonyl) -1H-indole-2-carbonyl] -3-dimethylamino-acrylonitrile 490, 492
- 1137 1137
- Ó n / 3-dimetilamino-2-[6-piridin-2-il-1-(tolueno-4- sulfonil)-1H- indol-2-carbonil]-acrilonitrilo 471 Ó n / 3-dimethylamino-2- [6-pyridin-2-yl-1- (toluene-4-sulfonyl) -1H- indole-2-carbonyl] -acrylonitrile 471
- 1138 1138
- 0 ,-rC0 vA<J>-yJ„ ft- j1 2-[5-ciclopropil-1-(tolueno-4-sulfonil) -1 H-indol-2- carbonil]-3-dimetilamino-acrilonitrilo 434 0, -rC0 vA <J> -yJ „ft- j1 2- [5-cyclopropyl-1- (toluene-4-sulfonyl) -1 H-indole-2-carbonyl] -3-dimethylamino-acrylonitrile 434
- 1139 1139
- N- ¿ 2-(6-tert-butil-1H-indol-2-carbonil)-3-dimetilamino- acrilonitrilo 296 N- ¿2- (6-tert-butyl-1H-indole-2-carbonyl) -3-dimethylamino-acrylonitrile 296
- 1140 1140
- r, r|| u<Síq N*\í¡HL M- 3-dimetilamino-2-[6-piridazin-3-il-1-(tolueno-4-sulfonil)- 1 H-indol-2-carbonil] -acrilonitrilo 472 r, r || u <Siq N * \ HL M- 3-dimethylamino-2- [6-pyridazin-3-yl-1- (toluene-4-sulfonyl) -1 H-indole-2-carbonyl] -acrylonitrile 472
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1141 1141
- H F¿Tf^N F^F Ni 3-dimetilamino-2-(5-fluoro-4-trifluorometil-1H- indol-2-carbonil] -acrilonitrilo 324 [MH] H F ¿Tf ^ N F ^ F Ni 3-dimethylamino-2- (5-fluoro-4-trifluoromethyl-1H- indole-2-carbonyl] -acrylonitrile 324 [MH]
- 1142 1142
- H N— i 3-dimetilamino-2-(5-fenoxi-1H-indol-2-carbonil]- acrilonitrilo 332 H N— i 3-dimethylamino-2- (5-phenoxy-1H-indole-2-carbonyl] - acrylonitrile 332
- 1143 1143
- " i 3-dimetilamino-2-[6-metilsulfanil-1-(tolueno-4- sulfonil)-1 H-indol-2-carbonil] -acrilonitrilo 440 "i 3-dimethylamino-2- [6-methylsulfanyl-1- (toluene-4- sulfonyl) -1 H-indol-2-carbonyl] -acrylonitrile 440
- 1144 1144
- f"Y*yJ ^ y 3-dimetilamino-2-(5-imidazol-1-il-1H -indol-2- carbonil)-acrilonitrilo 306 f "Y * yJ ^ y 3-dimethylamino-2- (5-imidazol-1-yl-1 H -indole-2-carbonyl) -acrylonitrile 306
- 1145 1145
- 3-dimetilamino-2-(5-trifluorometilsulfanil-1H- indol-2-carbonil)-acrilonitrilo 340 3-dimethylamino-2- (5-trifluoromethylsulfanyl-1H- indole-2-carbonyl) -acrylonitrile 340
- 1146 1146
- H i ¡u 3-dimetilamino-2-(6-yodo-1H-indol-2-carbonil)- acrilonitrilo M no detectado H i ¡u 3-dimethylamino-2- (6-iodo-1H-indole-2-carbonyl) - acrylonitrile M not detected
- 1147 1147
- H rt / (2-(4-tert-butil-1H-indol-2-carbonil) -3- dimetilamino-acrilonitrilo 296 Hrt / (2- (4-tert-butyl-1H-indole-2-carbonyl) -3-dimethylamino-acrylonitrile 296
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1148 1148
- Q N— / 3-dimetilamino-2-(5-metil-1 H-indol -2-carbonil)- acrilonitrilo 254 Q N— / 3-dimethylamino-2- (5-methyl-1 H-indole -2-carbonyl) - acrylonitrile 254
- 1149 1149
- í- / 3-dimetilamino-2-(5-etil-1 H-indol-2- carbonil)- acrilonitrilo 268 í- / 3-dimethylamino-2- (5-ethyl-1 H-indole-2-carbonyl) - acrylonitrile 268
- 1150 1150
- fp a- r 2-[5-butoxi-1-(tolueno-4-sulfonil)-1H-indol-2- carbonil]- 3-dimetilamino-acrilonitrilo 466 fp a- r 2- [5-butoxy-1- (toluene-4-sulfonyl) -1H-indole-2-carbonyl] - 3-dimethylamino-acrylonitrile 466
- 1151 1151
- &:SoA JvC&í*, N- 3-dimetilamino-2-[5-isopropoxi-1-(tolueno-4-sulfonil)- 1H-indol-2-carbonil]-acrilonitrilo 452 &: SoA JvC & í *, N- 3-dimethylamino-2- [5-isopropoxy-1- (toluene-4-sulfonyl) -1H-indole-2-carbonyl] -acrylonitrile 452
- 1152 1152
- .o-^oV^Uti 3-dimetilamino-2-[5-(2-metoxi-etoxi)- 1-(tolueno-4- sulfonil)-1 H-indol-2- carbonil]-acrilonitrilo 467.99 .o- ^ oV ^ Uti 3-dimethylamino-2- [5- (2-methoxy-ethoxy) -1- (toluene-4-sulfonyl) -1 H-indole-2-carbonyl] -acrylonitrile 467.99
- 1153 1153
- °-p ‘N- / 2-(1-bencenosulfonil-4-metil-1H-indol-2- carbonil)-3- dimetilamino-acrilonitrilo 394 ° -p ‘N- / 2- (1-benzenesulfonyl-4-methyl-1H-indole-2-carbonyl) -3- dimethylamino-acrylonitrile 394
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1154 1154
- H — f 3 -dimetilamino-2-(5-fluoro-6-trifluorometil-1H-indol- 2- carbonil)-acrilonitrilo 324 [MH] H-f 3-dimethylamino-2- (5-fluoro-6-trifluoromethyl-1H-indole-2-carbonyl) -acrylonitrile 324 [MH]
- 1155 1155
- H ^ N- 4 3-dimetilamino-2-(6-fluoro-5-metoxi -1 H-indol- 2- carbonil)-acrilonitrilo 288 H ^ N- 4 3-dimethylamino-2- (6-fluoro-5-methoxy -1 H-indole-2-carbonyl) -acrylonitrile 288
- 1156 1156
- OjOS^z, j^ 2-[5-bencil-1-(tolueno-4-sulfonil)-1H-indol-2-carbonil]-3- dimetilamino-acrilonitrilo 484 EYES ^ z, j ^ 2- [5-benzyl-1- (toluene-4-sulfonyl) -1H-indole-2-carbonyl] -3-dimethylamino-acrylonitrile 484
- 1157 1157
- N- / 2-(6-cloro-5-metoxi-1H-indol-2-carbonil)-3- dimetilamino-acrilonitrilo 304, 306 N- / 2- (6-Chloro-5-methoxy-1H-indole-2-carbonyl) -3-dimethylamino-acrylonitrile 304, 306
- 1158 1158
- H n- / 2-(5-cloro-6-metoxi-1H-indol-2-carbonil)-3- dimetilamino-acrilonitrilo 304, 306 H n- / 2- (5-chloro-6-methoxy-1H-indole-2-carbonyl) -3-dimethylamino-acrylonitrile 304, 306
- 1159 1159
- H J .. N-*rX js&Ií V 3-dimetilamino-2-(6-isopropoxi-1 H-indol-2-carbonil] - acrilonitrilo 298 H J .. N- * rX js & II V 3-dimethylamino-2- (6-isopropoxy-1 H-indole-2-carbonyl] - acrylonitrile 298
- 1160 1160
- ■H' ii *í- 2-(1-bencenosulfonil-4-trimetilsilaniletinil-1 H-indol-2- carbonil)-3-dimetilaminoacrilonitrilo 476 ■ H 'ii * í- 2- (1-benzenesulfonyl-4-trimethylsilanyletinyl-1 H-indole-2-carbonyl) -3-dimethylaminoacrylonitrile 476
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1161 1161
- h- 2-[5-bromo-6-metoxi-1-(tolueno-4-sulfonil)-1H-indol-2- carbonil]-3-dimetilamino-acrilonitrilo 502, 504 h- 2- [5-Bromo-6-methoxy-1- (toluene-4-sulfonyl) -1H-indole-2-carbonyl] -3-dimethylamino-acrylonitrile 502, 504
- 1162 1162
- 0 f 3-dimetilamino-2-[5-(tolueno-4-sulfonil)-5H- [1,3]]dioxolo[4,5-f] indol-6-carbonil] —acrilonitrilo 438 0 f 3-dimethylamino-2- [5- (toluene-4-sulfonyl) -5H- [1,3]] dioxolo [4,5-f] indole-6-carbonyl] —acrylonitrile 438
- 1163 1163
- CU'CÓ-C-1 f ■ N— / 2-(6-benciloxi-1 H-indol-2-carbonil) -3-dimetilamino- acrilonitrilo 346 CU'CÓ-C-1 f ■ N— / 2- (6-benzyloxy-1 H-indole-2-carbonyl) -3-dimethylamino-acrylonitrile 346
- 1164 1164
- Ó °s0 M- t 2-[5-ciclopropilmetoxi-1-(tolueno-4-sulfonil)-1H-indol-2- carbonil]-3-dimetilaminoacrilonitrilo 464 Ó ° s0 M- t 2- [5-cyclopropylmethoxy-1- (toluene-4-sulfonyl) -1H-indole-2-carbonyl] -3-dimethylaminoacrylonitrile 464
- 1165 1165
- ^ ,c r 3-dimetilamino-2-(4-isopropoxi-1H-indol-2-carbonil)- acrilonitrilo 298 ^, c r 3-dimethylamino-2- (4-isopropoxy-1H-indole-2-carbonyl) - acrylonitrile 298
- 1166 1166
- 0^=0 Q Br 2-(1-bencenosulfonil-4-bromo-1H-indol -2-carbonil)-3- dimetilamino-acrilonitrilo 458, 460 0 ^ = 0 Q Br 2- (1-benzenesulfonyl-4-bromo-1H-indole -2-carbonyl) -3- dimethylamino-acrylonitrile 458, 460
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1167 1167
- r O pX 1 F Q A—=M N- 2-[2,2-difluoro-5-(tolueno-4-sulfonil) -5H- [1,3]dioxolo[4,5-f]indol-6-carbonil] -3-dimetilamino- acrilonitrilo 474 r O pX 1 FQA— = M N- 2- [2,2-difluoro-5- (toluene-4-sulfonyl) -5H- [1,3] dioxolo [4,5-f] indole-6-carbonyl] -3-dimethylamino acrylonitrile 474
- 1168 1168
- . £} r T 0,$--o ^ iPt'V-f N- f 2-[6-(3-cloro-piridin-2-il)-1-(tolueno-4-sulfonil)-1 H-indol- 2-carbonil]-3-dimetilaminoacrilonitrilo 505, 507 . £} r T 0, $ - o ^ iPt'Vf N- f 2- [6- (3-chloro-pyridin-2-yl) -1- (toluene-4-sulfonyl) -1 H-indole- 2 -carbonyl] -3-dimethylaminoacrylonitrile 505, 507
- 1169 1169
- , Ó °cX H — / 3-dimetilamino-2-[6-(3-fluoropiridin -2-il)-1 -(tolueno-4- sulfonil)-1 H-indol -2-carbonil] —acrilonitrilo 489 , ° CX H - / 3-dimethylamino-2- [6- (3-fluoropyridin -2-yl) -1 - (toluene-4- sulfonyl) -1 H-indole -2-carbonyl] —acrylonitrile 489
- 1170 1170
- $ N- / 3-dimetilamino-2-[6-metil-1-(tolueno -4-sulfonil)-1H- indol-2-carbonil]-acrilonitrilo 408 N- / 3-dimethylamino-2- [6-methyl-1- (toluene -4-sulfonyl) -1H- indole-2-carbonyl] -acrylonitrile 408
- 1171 1171
- ■ Y< Y* — f 3-dimetilamino-2-[6-(5-fluoro-piridin -2-il)-1 -(tolueno-4- sulfonil)-1 H-indol -2-carbonil]-acrilonitrilo 489 ■ Y <Y * - f 3-dimethylamino-2- [6- (5-fluoro-pyridin -2-yl) -1 - (toluene-4- sulfonyl) -1 H-indole -2-carbonyl] -acrylonitrile 489
- 1172 1172
- QOH* N- 2-(2,3-dihidro-6H-[1,4]dioxino[2,3-f] indol-7-carbonil)-3- dimetilamino-acrilonitrilo 298 QOH * N- 2- (2,3-dihydro-6H- [1,4] dioxino [2,3-f] indole-7-carbonyl) -3-dimethylamino-acrylonitrile 298
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1173 1173
- O & N — 3-dimetilamino-2-[6-(6-morfolin-4-il-piridazin- 3-il)-1- (tolueno-4-sulfonil) -1 H-indol-2- carbonil]-acrilonitrilo 557 O & N - 3-dimethylamino-2- [6- (6-morpholin-4-yl-pyridazin-3-yl) -1- (toluene-4-sulfonyl) -1 H-indole-2-carbonyl] -acrylonitrile 557
- 1174 1174
- $ A °'S- 0XCy-J^, w- 2-[5-cloro-6-cidopropilmetoxi-1-(tolueno-4- sulfonil)-1H- indol-2-carbonil]-3-dimetilaminoacrilonitrilo 498, 500 A ° 'S- 0XCy-J ^, w- 2- [5-chloro-6-cidopropylmethoxy-1- (toluene-4- sulfonyl) -1H- indole-2-carbonyl] -3-dimethylaminoacrylonitrile 498, 500
- 1175 1175
- p ÍNI— /■ 2-(4,6-di-tert-butil-1H-indol-2-carbonil)-3-dimetilamino- acrilonitrilo 352 pIN— / ■ 2- (4,6-di-tert-butyl-1H-indole-2-carbonyl) -3-dimethylamino-acrylonitrile 352
- 1176 1176
- “n- y 3-dimetilamino-2-[1-(tolueno-4-sulfonil)-6-(5- trifluorometilpiridin -2-il)-1 H-indol-2- carbonil]-acrilonitrilo 539 "N- and 3-dimethylamino-2- [1- (toluene-4-sulfonyl) -6- (5- trifluoromethylpyridin -2-yl) -1 H-indole-2-carbonyl] -acrylonitrile 539
- 1177 1177
- ff n fVííí,Vvn p 3-dimethlamino-2-[1-(tolueno-4-sulfonil)-6-(6- trifluorometil-piridin -2-il)-1 H-indol-2- carbonil]-acrilonitrilo 539 ff n fVííí, Vvn p 3-dimethlamino-2- [1- (toluene-4-sulfonyl) -6- (6- trifluoromethyl-pyridin -2-yl) -1 H-indole-2-carbonyl] -acrylonitrile 539
- 1178 1178
- í 2-[6-(5-cloropiridin-2-il)-1-(tolueno -4-sulfonil)- 1 H-indol-2- carbonil] -3-dimetilaminoacrilonitrilo 505, 507 í 2- [6- (5-Chloropyridin-2-yl) -1- (toluene -4-sulfonyl) - 1 H-indole-2-carbonyl] -3-dimethylaminoacrylonitrile 505, 507
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1179 1179
- í a "V" -, & ■ ■ i 2-[4,5-dibromo-1-(4-metoxi-bencil) -1 H-pirrol- 2- carbonil)-3-dimetilamino-acrilonitrilo 466, 468, 470 í a "V" -, & ■ ■ i 2- [4,5-dibromo-1- (4-methoxy-benzyl) -1 H-pyrrol-2- carbonyl) -3-dimethylamino-acrylonitrile 466, 468, 470
- 1180 1180
- F Ó / 3-dimetilamino-2-[1-(tolueno-4-sulfonil)-6-(3- trifluorometil-piridin -2-il)-1 H-indol-2- carbonil]- acrilonitrilo 539 F Ó / 3-dimethylamino-2- [1- (toluene-4-sulfonyl) -6- (3- trifluoromethyl-pyridin -2-yl) -1 H-indole-2-carbonyl] - acrylonitrile 539
- 1181 1181
- Y Ó rni / 3-dimetilamino-2-[1-(tolueno-4-sulfonil)-6-(4- trifluorometil-piridin -2-il)-1 H-indol-2- carbonil]- acrilonitrilo 539 Y Ó rni / 3-dimethylamino-2- [1- (toluene-4-sulfonyl) -6- (4- trifluoromethyl-pyridin -2-yl) -1 H-indole-2-carbonyl] - acrylonitrile 539
- 1182 1182
- / 3-dimetilamino-2-(5-metilsulfanil -1 H-indol-2- carbonil)-acrilonitrilo 286 / 3-dimethylamino-2- (5-methylsulfanyl -1 H-indole-2-carbonyl) -acrylonitrile 286
- 1183 1183
- >xxH- / 3-dimetilamino-2-(5-metanosulfonilo -1 H-indol- 2-carbonil)-acrilonitrilo 318 > xxH- / 3-dimethylamino-2- (5-methanesulfonyl -1 H-indole-2-carbonyl) -acrylonitrile 318
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1184 1184
- £ sn- 2-(1-bencenosulfonil-4-isopropil-1H-indol-2- carbonil)-3- dimetilamino-acrilonitrilo 422 £ sn- 2- (1-benzenesulfonyl-4-isopropyl-1H-indole-2-carbonyl) -3-dimethylamino-acrylonitrile 422
- 1528 1528
- v. 2-[6-cloro-1-(tolueno-4-sulfonil)-1H-indol-2-carboml]-3- dimetilamino-acrilonitrilo 428 v. 2- [6-Chloro-1- (toluene-4-sulfonyl) -1H-indole-2-carboml] -3- dimethylamino-acrylonitrile 428
- 1529 1529
- t ó 1 2-[5-cloro-1-(tolueno-4-sulfonil)-1H-indol-2-carboml]-3- dimetilamino-acrilonitrilo 428 t or 1 2- [5-chloro-1- (toluene-4-sulfonyl) -1H-indole-2-carboml] -3- dimethylamino-acrylonitrile 428
- 1530 1530
- ° \ 3-dimetilamino-2-[1-(tolueno-4-sulfonil)-1H-mdol-3- carbonil]-acrilonitrilo 394 ° \ 3-dimethylamino-2- [1- (toluene-4-sulfonyl) -1H-mdol-3- carbonyl] -acrylonitrile 394
- 1531 1531
- t¡s 0=SJD ú □ Q^rV-*N SsT 1 3-dimetilamino-2-[1-(tolueno-4-sulfonil)-1H-indol- 6- carbonil]-acrilonitrilo 394 t¡s 0 = SJD ú □ Q ^ rV- * N SsT 1 3-dimethylamino-2- [1- (toluene-4-sulfonyl) -1H-indole-6- carbonyl] -acrylonitrile 394
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1532 1532
- ó N- / 2-[5-bromo-6-fluoro-1-(tolueno-4-sulfonil)-1H-indol- 2- carbonil]-3-dimetilaminoacrilonitrilo 490, 492 or N- / 2- [5-bromo-6-fluoro-1- (toluene-4-sulfonyl) -1H-indole-2-carbonyl] -3-dimethylaminoacrylonitrile 490, 492
- 1533 1533
- %o F N- 3-dimetilamino-2-[1-(tolueno-4-sulfonil)-5- trifluorometil- 1 H-indol-2- carbonil]-acrilonitrilo 462 % or F N- 3-dimethylamino-2- [1- (toluene-4-sulfonyl) -5-trifluoromethyl- 1 H-indole-2-carbonyl] -acrylonitrile 462
- 1534 1534
- ú ■3rQ N" { 3-dimetilamino-2-[1-(tolueno-4-sulfonil)-5- trifluorometoxi-1 H-indol-2- carbonil]-acrilonitrilo 478 ú ■ 3rQ N "{3-dimethylamino-2- [1- (toluene-4-sulfonyl) -5- trifluoromethoxy-1 H-indole-2-carbonyl] -acrylonitrile 478
- 1535 1535
- 6 ü-^ s-0 “VK-. Cl V f 2-[4,6-dicloro-1-(tolueno-4-sulfonil)-1H-indol- 2- carbonil]-3-dimetilaminoacrilonitrilo 462 6 ü- ^ s-0 “VK-. Cl V f 2- [4,6-dichloro-1- (toluene-4-sulfonyl) -1H-indole-2-carbonyl] -3-dimethylaminoacrylonitrile 462
- 1536 1536
- i 2-[6-bromo-4-fluoro-1-(tolueno-4-sulfonil)-1H-indol-2- carbonil]-3-dimetilaminoacrilonitrilo 490 i 2- [6-Bromo-4-fluoro-1- (toluene-4-sulfonyl) -1H-indole-2-carbonyl] -3-dimethylaminoacrylonitrile 490
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1537 1537
- f FtF >1" / 3-dimetilamino-2-[1-(tolueno-4-sulfonil)-6- trifluorometoxi-1H- indol-2- carbonil]-acrilonitrilo 478 f FtF> 1 "/ 3-dimethylamino-2- [1- (toluene-4-sulfonyl) -6- trifluoromethoxy-1H- indole-2-carbonyl] -acrylonitrile 478
- 1538 1538
- é e,XX^M N-*" f 2-[5,6-dicloro-1-(tolueno-4-sulfonil)-1H-indol- 2-carbonil]-3- dimetilaminoacrilonitrilo 462 é e, XX ^ M N- * "f 2- [5,6-dichloro-1- (toluene-4-sulfonyl) -1H-indole-2-carbonyl] -3- dimethylaminoacrylonitrile 462
- 1539 1539
- i oO r° N— í 2-[4,5-dicloro-1-(tolueno-4-sulfonil)-1H-indol- 2-carbonil]-3- dimetilaminoacrilonitrilo 462 i oO r ° N— í 2- [4,5-dichloro-1- (toluene-4-sulfonyl) -1H-indole-2-carbonyl] -3- dimethylaminoacrylonitrile 462
- 1540 1540
- Ó VX- y 2-[4,6-difluoro-1-(tolueno-4-sulfonil)-1H-indol- 2-carbonil]-3- dimetilaminoacrilonitrilo 430 Ó VX- and 2- [4,6-Difluoro-1- (toluene-4-sulfonyl) -1H-indole-2-carbonyl] -3- dimethylaminoacrylonitrile 430
- 1541 1541
- qoP N V i 2-(benzofurano-2-carbonil)-3-dimetilaminoacrilonitrilo 241 qoP N V i 2- (benzofuran-2-carbonyl) -3-dimethylaminoacrylonitrile 241
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1542 1542
- 0>VN V 1 2-(benzo[b]tiofeno-2-carbonil)-3- dimetilamino- acrilonitrilo 257 0> VN V 1 2- (benzo [b] thiophene-2-carbonyl) -3-dimethylamino-acrylonitrile 257
- 1543 1543
- W^M T Sr i 2-(benzotiazol-2-carbonil)-3- dimetilamino-acrilonitrilo 258 W ^ M T Sr i 2- (benzothiazol-2-carbonyl) -3- dimethylamino-acrylonitrile 258
- 1544 1544
- 0 l 3-dimetilamino-2-(4-fluorobenzoil)- acrilonitrilo 219 0 1 3-dimethylamino-2- (4-fluorobenzoyl) - acrylonitrile 219
- 1545 1545
- cu 9 PyA^N i 2-(3-cloro-benzolil)-3-dimetilaminoacrilonitrilo 235 cu 9 PyA ^ N i 2- (3-chloro-benzolyl) -3-dimethylaminoacrylonitrile 235
- 1546 1546
- P Cryv®N N i 3-dimetilamino-2-(quinolina-3-carbonil)-acrilonitrilo 252 P Cryv®N N i 3-dimethylamino-2- (quinoline-3-carbonyl) -acrylonitrile 252
- 1547 1547
- r'N 0 f ^ V 1 3-dimetilamino-2-(quinolina-7- carbonil)-acrilonitrilo 252 r'N 0 f ^ V 1 3-dimethylamino-2- (quinoline-7- carbonyl) -acrylonitrile 252
- 1548 1548
- ^ 0 ryvuN || VN" 1 3-dimetilamino-2-(quinolina-6- carbonil)-acrilonitrilo 252 ^ 0 ryvuN || VN "1 3-dimethylamino-2- (quinoline-6- carbonyl) -acrylonitrile 252
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1549 1549
- H O M V I 3-d¡metilam¡no-2-(1H-indol-2- carbonil)-acrilonitrilo 240 H O M V I 3-dmethylamine-2- (1H-indole-2-carbonyl) -acrylonitrile 240
Etapa 3: Síntesis del 3-(1-bencenosulfonil-1H-¡ndol-2-¡l)-3-oxo-prop¡onitrilo (1185)Stage 3: Synthesis of 3- (1-benzenesulfonyl-1H-landol-2-1) -3-oxo-propitonitrile (1185)
5 Se adicionó acetonitrilo (10.6 g, 0.202 mol) a una solución en tetrahidrofurano (THF) (135 mi) del áster etílico del ácido 1-bencenosulfonil- 1H-indol-2-carboxílico (33.4 g, 0.101 mol), y se enfrió a -78°C. Una solución en tetrahidrofurano (THF) de litio bis(trimetilsilil) amida 1 M (213 mi, 0.213 mol) se adicionó gota a gota a esta, y se agitó, durante 30 minutos. Una solución acuosa saturada (83 mi) de cloruro de amonio se adicionó a la mezcla de reacción, y se agitó, durante 10 minutos. Se adicionó agua (50 mi) a la mezcla y se calentó a temperatura ambiente. 10 El solvente se separó por destilación bajo presión reducida, y el residuo resultante se extrajo con acetato de etilo. El extracto se lavó con una solución acuosa saturada de cloruro de sodio y se secó sobre sulfato de sodio anhidro. El desecante se eliminó por filtración. El filtrado se concentró bajo presión reducida. El producto en bruto resultante se lavó con etanol para dar el 3-(1-bencenosulfon¡l-1H-¡ndol-2-il)-3-oxo-propionitrilo (47.3 g, 70%).5 Acetonitrile (10.6 g, 0.202 mol) was added to a solution in tetrahydrofuran (THF) (135 ml) of the 1-benzenesulfonyl-1H-indole-2-carboxylic acid ethyl ester (33.4 g, 0.101 mol), and cooled at -78 ° C. A solution in 1 M tetrahydrofuran (THF) lithium bis (trimethylsilyl) amide (213 mL, 0.213 mol) was added dropwise thereto, and stirred, for 30 minutes. A saturated aqueous solution (83 ml) of ammonium chloride was added to the reaction mixture, and stirred, for 10 minutes. Water (50 ml) was added to the mixture and heated to room temperature. The solvent was distilled off under reduced pressure, and the resulting residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting crude product was washed with ethanol to give 3- (1-benzenesulfonyl-1H-¡ndol-2-yl) -3-oxo-propionitrile (47.3 g, 70%).
1H-RMN (CDCIs) 8: 8.12 (1 .OH, dq, J = 8.5, 0.8 Hz), 7.79-7.76(2.0H,m), 7.56-7.48 (3.0H, m), 7.42-7.38 (2.0H, m), 15 7.32-7.28 (1 .OH, m), 7.20 (1.0H, d, J = 0.8 Hz), 4.16 (2.0H, s) ESI (LC-MS modo positivo) m/z 325 [(M+H)+]1 H-NMR (CDCIs) 8: 8.12 (1 .OH, dq, J = 8.5, 0.8 Hz), 7.79-7.76 (2.0H, m), 7.56-7.48 (3.0H, m), 7.42-7.38 (2.0H , m), 15 7.32-7.28 (1 .OH, m), 7.20 (1.0H, d, J = 0.8 Hz), 4.16 (2.0H, s) ESI (LC-MS positive mode) m / z 325 [( M + H) +]
Los compuestos de los números 1186 a 1284, y 1550 a 1571 enumerados en la Tabla 10, se sintetizaron mediante el mismo método como en la Etapa 3.The compounds of numbers 1186 to 1284, and 1550 to 1571 listed in Table 10, were synthesized by the same method as in Step 3.
Tabla 10Table 10
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1186 1186
- O °s=o croK. 3-(1-bencenosulfonil-6-morfolin-4-ilmetil-1H-indol- 2-il)-3- oxo-propionitrilo 424 O ° s = or croK. 3- (1-Benzenesulfonyl-6-morpholin-4-ylmethyl-1H-indol-2-yl) -3-oxo-propionitrile 424
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1187 1187
- 3-(1-bencenosulfonil-5-morfolin-4-ilmetil-1H-indol- 2-il)-3- oxo-propionitrilo 424 3- (1-Benzenesulfonyl-5-morpholin-4-ylmethyl-1H-indol-2-yl) -3-oxo-propionitrile 424
- 1188 1188
- Q 0 3-(1-bencenosulfonil-4-morfolin-4-il-1H-indol-2-il)-3-oxo- propionitrilo 410 Q 0 3- (1-benzenesulfonyl-4-morpholin-4-yl-1H-indol-2-yl) -3-oxo-propionitrile 410
- 1189 1189
- Q <o 3-(1-bencenosulfonil-4-morfolin-4-ilmetil-1H-indol- 2-il)-3- oxo-propionitrilo 424 Q <or 3- (1-benzenesulfonyl-4-morpholin-4-ylmethyl-1H-indole-2-yl) -3- oxo-propionitrile 424
- 1190 1190
- 2. tert-butil éster del ácido 4-[1-bencenosulfonil-2-(2- cianoacetil) -1 H-indol- 5-ilmetil]-piperazina-1-carboxílico 523 2. 4- [1-Benzenesulfonyl-2- (2- cyanoacetyl) -1 H-indol-5-ylmethyl] -piperazine-1-carboxylic acid tert-butyl ester 523
- 1191 1191
- 0 s=o 3-(1-bencenosulfonil-4-fluoro-1H-indol-2-il)-3-oxo- propionitrilo 343 0 s = or 3- (1-benzenesulfonyl-4-fluoro-1H-indole-2-yl) -3-oxo-propionitrile 343
- 1192 1192
- Q C-'S=0 fI5PL* 3-(1-bencenosulfonil-5-fluoro-1H-indol-2-il)-3-oxo- propionitrilo 343 Q C-'S = 0 fI5PL * 3- (1-benzenesulfonyl-5-fluoro-1H-indole-2-yl) -3-oxo-propionitrile 343
- 1193 1193
- p °vT 3-(1-bencenosulfonil-6-fluoro-1H-indol-2-il)-3-oxo- propionitrilo 343 p ° vT 3- (1-benzenesulfonyl-6-fluoro-1H-indole-2-yl) -3-oxo-propionitrile 343
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1194 1194
- d °-s'=o 3-( 1 -bencenosulfonil-1 H-pirrolo[2,3-b]pi ridin-2-il)-3- oxo-propionitrilo 340 d ° -s' = or 3- (1-benzenesulfonyl-1 H -pyrrolo [2,3-b] pi ridin-2-yl) -3- oxo-propionitrile 340
- 1195 1195
- P °-'s=o (¡'"YW3 \__ 3-(1-bencenosulfonil-1H-pirrolo[3,2-c] piridin-2-il)-3- oxo-propionitrilo 326 P ° -'s = o (¡'"YW3 \ __ 3- (1-benzenesulfonyl-1H-pyrrolo [3,2-c] pyridin-2-yl) -3- oxo-propionitrile 326
- 1196 1196
- Q °'>=0 r^w^YVJ* 3-(1-bencenosulfonil-5-fluoro-6-morfolin-4-ilmetil-1H- indol-2-il)-3 -oxo-propionitrilo 442 Q ° '> = 0 r ^ w ^ YVJ * 3- (1-benzenesulfonyl-5-fluoro-6-morpholin-4-ylmethyl-1H- indole-2-yl) -3 -oxo-propionitrile 442
- 1197 1197
- p sí? Or^XXHL„ 3-[1-bencenosulfonil-6-(2-morfolin-4-il-etoxi)- 1H- indol-2-il]-3-oxo-propionitrilo 454 yes yes? Or ^ XXHL „3- [1-benzenesulfonyl-6- (2-morpholin-4-yl-ethoxy) - 1 H- indol-2-yl] -3-oxo-propionitrile 454
- 1198 1198
- P °’S = 0 axó-c. 3-[1-bencenosulfonil-6-(tetrahidro-piran -4-iloxi)- 1H- indol-2-il]-3-oxo-propionitrilo 425 P ° ’S = 0 axó-c. 3- [1-Benzenesulfonyl-6- (tetrahydro-pyran -4-yloxy) - 1H- indole-2-yl] -3-oxo-propionitrile 425
- 1199 1199
- CE 3-[4-cloro-1-(tolueno-4-sulfonil)-1H-indol-2-il] -3 -oxo- propionitrilo 373, 375 CE 3- [4-Chloro-1- (toluene-4-sulfonyl) -1H-indole-2-yl] -3-oxo-propionitrile 373, 375
- 1200 1200
- ^¿o OH- 3-[3-fluoro-1-(tolueno-4-sulfonil)-1H-indol-2-il]-3- oxo- propionitrilo 357 ^ ¿Or OH- 3- [3-fluoro-1- (toluene-4-sulfonyl) -1H-indole-2-yl] -3- oxo-propionitrile 357
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1201 1201
- 3-[5-(1-metil-piperidi n-4-il)-1 -(tolueno-4- sulfonil)-1H- indol-2-il]-3-oxo-propionitrilo 436 3- [5- (1-methyl-piperidi n-4-yl) -1 - (toluene-4-sulfonyl) -1H- indole-2-yl] -3-oxo-propionitrile 436
- 1202 1202
- 6 tert-butil éster del ácido 4-[2-(2-ciano-acetil)-6-fluoro- 1-(tolueno-4- sulfonil)-1 H-indol-5-il] -3,6-dihidro-2H- piridina-1- carboxílico 538 6 4- [2- (2-Cyano-acetyl) -6-fluoro-1- (toluene-4- sulfonyl) -1 H-indol-5-yl] -3,6-dihydro- acid tert-butyl ester 2H- pyridine-1- carboxylic 538
- 1203 1203
- Cr* ° 1 D tert-butil éster del ácido 4-[2-(2-ciano-acetil)-1- (tolueno-4-sulfonil)-1H-indol- 5-il]-piperidina-1- carboxílico 466 [MtBu] Cr * ° 1 D 4- [2- (2-Cyano-acetyl) -1- (toluene-4-sulfonyl) -1H-indole-5-yl] -piperidine-1-carboxylic acid tert-butyl ester 466 [ MtBu]
- 1204 1204
- ¡ P °^ea -OjQ>u. 3-[5-((R)-3-fluoro-pirrolidin-1 -ilmetil) -1-(tolueno- 4- sulfonil)-1 H-indol-2-il] -3-oxo-propionitrilo 440 ¡P ° ^ ea -OjQ> u. 3- [5 - ((R) -3-Fluoro-pyrrolidin-1-methylmethyl) -1- (toluene-4-sulfonyl) -1 H-indol-2-yl] -3-oxo-propionitrile 440
- 1205 1205
- W'^ 1 <J tert-butil éster del ácido 4-[2-(2-ciano-acetil)-6-fluoro- 1-(tolueno-4- sulfonil)-1 H-indol-5-il] -piperidina-1- carboxílico 540 W '^ 1 <J tert-butyl ester of 4- [2- (2-cyano-acetyl) -6-fluoro-1- (toluene-4- sulfonyl) -1 H-indole-5-yl] -piperidine -1- carboxylic 540
- 1206 1206
- ,r* K.-0,.5--;; _N._J 3-[6-fluoro-5-(1-metil-pi peridin-4-il) -1-(tolueno-4- sulfonil)-1 H-indol-2-il] -3-oxo-propionitrilo 454 , r * K.-0, .5-- ;; _N._J 3- [6-fluoro-5- (1-methyl-pi peridin-4-yl) -1- (toluene-4- sulfonyl) -1 H-indole-2-yl] -3-oxo-propionitrile 454
- 1207 1207
- P y?^T°c - xcl>-u 3-[1-bencenosulfonil-6-(tert-butil-difenilsilaniloximetil)- 1 H-indol -2-il]-3-oxo-propionitrilo 593 P y? ^ T ° c - xcl> -u 3- [1-benzenesulfonyl-6- (tert-butyl-diphenylsilanyloxymethyl) -1 H-indole -2-yl] -3-oxo-propionitrile 593
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1208 1208
- Y«J 3-[5-(1-isopropil-piperidin-4-il)-1-(tolueno-4- sulfonil)-1H- indol-2-il] -3-oxo-propionitrilo 64 Y «J 3- [5- (1-isopropyl-piperidin-4-yl) -1- (toluene-4- sulfonyl) -1H- indole-2-yl] -3-oxo-propionitrile 64
- 1209 1209
- £ ?r'*rN Q0 Í^JCCK^ 3-[6-fluoro-5-(1-isopropil-piperidin-4-il)-1-(tolueno- 4- sulfonil)-1 H-indol-2-il] -3-oxo-propionitrilo 482 £? R '* rN Q0 Í ^ JCCK ^ 3- [6-fluoro-5- (1-isopropyl-piperidin-4-yl) -1- (toluene- 4- sulfonyl) -1 H-indole-2-yl ] -3-oxo-propionitrile 482
- 1210 1210
- p jO^CíK» 3-{1-bencenosulfonN-6-[2-(4-metN-piperadin-1-N)-etoxi]-1H- indol-2-il} -3-oxo-propionitrilo 467 p jO ^ CíK »3- {1-benzenesulfonN-6- [2- (4-metN-piperadin-1-N) -ethoxy] -1H- indole-2-yl} -3-oxo-propionitrile 467
- 1211 1211
- 3-[6-fluoro-5-(4-metil-piperadin-1-ilmetil)- 1-(tolueno-4- sulfonil)-1H-indol-2-il]-3-oxo-propionitrilo 469 3- [6-Fluoro-5- (4-methyl-piperadin-1-ylmethyl) - 1- (toluene-4- sulfonyl) -1H-indole-2-yl] -3-oxo-propionitrile 469
- 1212 1212
- ó °So 3-[6-fluoro-5-pirrolidin-1-ilmetil)-1-(tolueno-4- sulfonil)-1H- indol-2-il]-3-oxo-propionitrilo 440 or ° So 3- [6-fluoro-5-pyrrolidin-1-ylmethyl) -1- (toluene-4-sulfonyl) -1H- indole-2-yl] -3-oxo-propionitrile 440
- 1213 1213
- .. ó c 3-[6-(1-metil-piperidin-4-il)-1 -(tolueno-4- sulfonil)-1 H-indol- 2-il] -3-oxo-propionitrilo 436 .. or c 3- [6- (1-methyl-piperidin-4-yl) -1 - (toluene-4-sulfonyl) -1 H-indole-2-yl] -3-oxo-propionitrile 436
- 1214 1214
- í Q <rJ^ 3-[5-(1-ciclopentil-piperidin-4-il)-1-(tolueno-4- sulfonil)-1H- indol-2-il] -3 -oxo-propionitrilo 490 í Q <rJ ^ 3- [5- (1-cyclopentyl-piperidin-4-yl) -1- (toluene-4- sulfonyl) -1H- indole-2-yl] -3 -oxo-propionitrile 490
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1215 1215
- £ 3-[5-(1-ciclohexil-piperidin-4-il)-1-(tolueno-4- sulfonil)- 1 H-indol-2-il] -3-oxo-propionitrilo 504 £ 3- [5- (1-Cyclohexyl-piperidin-4-yl) -1- (toluene-4-sulfonyl) - 1 H-indol-2-yl] -3-oxo-propionitrile 504
- 1216 1216
- o=í=o 0 a/ 3-[4-bromo-1-(tolueno-4-sulfonil)-1H-pirrol-2-il]-3- oxo- propionitrilo 367, 369 o = í = o 0 a / 3- [4-bromo-1- (toluene-4-sulfonyl) -1H-pyrrol-2-yl] -3- oxo-propionitrile 367, 369
- 1217 1217
- ~óx** 3-oxo-3-[1-(tolueno-4-sulfonil)-1H-pirrol-2-il]- propionitrilo 289 ~ ox ** 3-oxo-3- [1- (toluene-4-sulfonyl) -1H-pyrrol-2-yl] - propionitrile 289
- 1218 1218
- o ^JL*UHL=n 3-(5-metoxi-1H-indol-2-il)-3-oxo-propionitrilo 215 or ^ JL * UHL = n 3- (5-methoxy-1H-indole-2-yl) -3-oxo-propionitrile 215
- 1219 1219
- o~i ?-ziJ 3-[6-butil-1-(tolueno-4-sulfonil)-1 H-indol-2-il]-3- oxo- propionitrilo 395 o ~ i? -ziJ 3- [6-butyl-1- (toluene-4-sulfonyl) -1 H-indole-2-yl] -3- oxo-propionitrile 395
- 1220 1220
- f| °*o_ F y^tV^' W 3-[5-(1-isopropil-pipendin-4-il)-1 -(tolueno-4- sulfonil)-6- trifluorometil-1 H-indol-2-il]-3-oxopropionitrilo 632 f | ° * o_ F and ^ tV ^ 'W 3- [5- (1-isopropyl-pipendin-4-yl) -1 - (toluene-4- sulfonyl) -6- trifluoromethyl-1 H-indole-2-yl] -3-oxopropionitrile 632
- 1221 1221
- H 3-(4,6-dimetoxi-1H-indol-2-il)-3-oxo-propionitrilo 245 H 3- (4,6-dimethoxy-1H-indole-2-yl) -3-oxo-propionitrile 245
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1222 1222
- H „ ,.o 3-(4-metoxi-1H-indol-2-il)-3-oxo-propionitrilo 215 H „, .o 3- (4-methoxy-1H-indole-2-yl) -3-oxo-propionitrile 215
- 1223 1223
- 3-(6-metoxi-1H-indol-2-il)-3-oxo-propionitrilo 215 3- (6-methoxy-1H-indole-2-yl) -3-oxo-propionitrile 215
- 1224 1224
- H 3-(4,6-dimetil-1H-indol-2-il)-3-oxo-propionitrilo 213 H 3- (4,6-dimethyl-1H-indole-2-yl) -3-oxo-propionitrile 213
- 1225 1225
- á <w XX/M_ 3-[6-bromo-1-(tolueno-4-sulfonil)-1H-indol-2-il]-3- oxo-propionitrilo 417, 449 á <w XX / M_ 3- [6-bromo-1- (toluene-4-sulfonyl) -1H-indole-2-yl] -3- oxo-propionitrile 417, 449
- 1226 1226
- i 9 Oig 0 3-[6-ciclopropil-1-(tolueno-4-sulfonil) -1H-indol-2-il]-3- oxo-propionitrilo 379 i 9 Oig 0 3- [6-cyclopropyl-1- (toluene-4-sulfonyl) -1H-indole-2-yl] -3- oxo-propionitrile 379
- 1227 1227
- 3-(5-tert-butil-1H-indol-2-il)-3-oxo-propionitrilo 241 3- (5-tert-butyl-1H-indol-2-yl) -3-oxo-propionitrile 241
- 1228 1228
- H ^ 3-(5-isopropil-1H-indol-2-il)-3-oxo-propionitrilo 227 H ^ 3- (5-Isopropyl-1H-indol-2-yl) -3-oxo-propionitrile 227
- 1229 1229
- T 1 T¿M 3-(5-benciloxi-1H-indol-2-il)-3-oxo-propionitrilo 291 T 1 T¿M 3- (5-benzyloxy-1H-indole-2-yl) -3-oxo-propionitrile 291
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1230 1230
- a'r 3-(4-benciloxi-1H-indol-2-il)-3-oxo-propionitrilo 291 a'r 3- (4-benzyloxy-1H-indol-2-yl) -3-oxo-propionitrile 291
- 1231 1231
- 0sS*c. 3-[5-bromo-1-(tolueno-4-sulfonil)-1H-indol-2-il] -3 - oxo-propionitrilo 417, 419 0sS * c. 3- [5-Bromo-1- (toluene-4-sulfonyl) -1H-indole-2-yl] -3-oxo-propionitrile 417, 419
- 1232 1232
- í_i COL, 3-(5,6-dimetoxi-1H-indol-2-il)-3-oxo-propionitrilo 245 Í_i COL, 3- (5,6-dimethoxy-1H-indole-2-yl) -3-oxo-propionitrile 245
- 1233 1233
- H a \r ] 3-(4-yodo-1H-indol-2-il)-3-oxo-propionitrilo 309 [MH] H a \ r] 3- (4-iodo-1H-indole-2-yl) -3-oxo-propionitrile 309 [MH]
- 1234 1234
- i OK_ 3-[6-isopropil-1-(tolueno-4-sulfonil) -1 H-indol-2-il]- 3-oxo-propionitrilo 381 i OK_ 3- [6-Isopropyl-1- (toluene-4-sulfonyl) -1 H-indole-2-yl] - 3-oxo-propionitrile 381
- 1235 1235
- „9 -s=o í COO 3-(1-bencenosulfonil-1H-pirrolo [3,2-b]pi ridin-2-il)- 3-oxo-propionitrilo 326 „9 -s = or í COO 3- (1-benzenesulfonyl-1H-pyrrolo [3,2-b] pi ridin-2-yl) - 3-oxo-propionitrile 326
- 1236 1236
- 3-[5-bromo-1-(tolueno-4-sulfonil)-6-trifluorometil- 1 H-indol-2-il]-3-oxo-propionitrilo 483, 485 [MH] 3- [5-Bromo-1- (toluene-4-sulfonyl) -6-trifluoromethyl- 1 H-indol-2-yl] -3-oxo-propionitrile 483, 485 [MH]
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1237 1237
- o=s=o o F 3-[6-bromo-5-fluoro-1-(tolueno-4-sulfonil)-1H-indol- 2- il]-3-oxo-propionitrilo 435, 437 o = s = o or F 3- [6-bromo-5-fluoro-1- (toluene-4-sulfonyl) -1H-indole-2-yl] -3-oxo-propionitrile 435, 437
- 1238 1238
- ó 3-oxo-3-[6-piridin-2-il-1-(tolueno-4-sulfonil)-1H-indol- 2-il]-propionitrilo 416 or 3-oxo-3- [6-pyridin-2-yl-1- (toluene-4-sulfonyl) -1H-indole-2-yl] -propionitrile 416
- 1239 1239
- í 0 cS-o 3-[5-ciclopropil-1-(tolueno-4-sulfonil) -1H-indol-2-il]-3- oxo-propionitrilo 379 í 0 cS-o 3- [5-cyclopropyl-1- (toluene-4-sulfonyl) -1H-indole-2-yl] -3- oxo-propionitrile 379
- 1240 1240
- 3-(6-tert-butil-1H-indol-2-il)-3-oxo-propionitrilo 241 3- (6-tert-butyl-1H-indol-2-yl) -3-oxo-propionitrile 241
- 1241 1241
- i n ^ o „ N;n 3-oxo-3-[6-piridazin-3-il-1-(tolueno-4-sulfonil)-1H- indol- 2-il]-propionitrilo 417 i n ^ o „N; n 3-oxo-3- [6-pyridazin-3-yl-1- (toluene-4-sulfonyl) -1H- indole-2-yl] -propionitrile 417
- 1242 1242
- H X^Cv^C F^F 3-(5-fluoro-4-trifluorometil-1 H-indol -2-il)-3- oxopropionitrilo 269 [MH] H X ^ Cv ^ C F ^ F 3- (5-fluoro-4-trifluoromethyl-1 H-indole -2-yl) -3- oxopropionitrile 269 [MH]
- 1243 1243
- H a0ccK,N 3-oxo-3-(5-fenoxi-1H-indol-2-il)-propionitrilo 277 H a0ccK, N 3-oxo-3- (5-phenoxy-1H-indole-2-yl) -propionitrile 277
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1244 1244
- Ó d-L 3-[6-metilsulfanil-1-(tolueno-4-sulfonil)-1H-indol- 2-il]-3- oxo-propionitrilo 385 Ó d-L 3- [6-Methylsulfanyl-1- (toluene-4-sulfonyl) -1H-indole-2-yl] -3- oxo-propionitrile 385
- 12456 12456
- 'U 3-(5-imidazol-1-il-1H-indol-2-il)-3 -oxo-propionitrilo 251 'U 3- (5-imidazol-1-yl-1H-indole-2-yl) -3-oxo-propionitrile 251
- 1246 1246
- F"f'F F 3-oxo-3-(5-trifluorometilsulfanil-1 H -indol-2-il)- propionitrilo 285 F "f'F F 3-oxo-3- (5-trifluoromethylsulfanyl-1 H -indole-2-yl) - propionitrile 285
- 1247 1247
- 3-(4-tert-butil-1H-indol-2-il)-3-oxo-propionitrilo 241 3- (4-tert-butyl-1H-indol-2-yl) -3-oxo-propionitrile 241
- 1248 1248
- P 3-(5-metil-1H-indol-2-il)-3-oxo-propionitrilo 199 P 3- (5-methyl-1H-indole-2-yl) -3-oxo-propionitrile 199
- 1249 1249
- H _ _ORLN 3-(5-etil-1H-indol-2-il)-3-oxo-propionitrilo 213 H _ _ORLN 3- (5-ethyl-1H-indole-2-yl) -3-oxo-propionitrile 213
- 1250 1250
- ó ~cjC6R 3-[5-butoxi-1-(tolueno-4-sulfonil)-1H-indol-2-il]-3- oxo- propionitrilo 411 or ~ cjC6R 3- [5-butoxy-1- (toluene-4-sulfonyl) -1H-indole-2-yl] -3- oxo-propionitrile 411
- 1251 1251
- oó 3-[5-isopropoxi-1-(tolueno-4-sulfonil) -1 H-indol-2-il]-3- oxo-propionitrilo 397 oó 3- [5-isopropoxy-1- (toluene-4-sulfonyl) -1 H-indol-2-yl] -3- oxo-propionitrile 397
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1252 1252
- o 0 = s'.0 3-[5-(2-metoxi-etoxi)-1-(tolueno-4-sulfonil)-1H- indol- 2-il]-3-oxo-propionitrilo 413 or 0 = s'.0 3- [5- (2-methoxy-ethoxy) -1- (toluene-4-sulfonyl) -1H- indole-2-yl] -3-oxo-propionitrile 413
- 1253 1253
- P °'s-o 3-(1-bencenosulfonil-4-metil-1H-indol-2-il)-3- oxo- propionitrilo 337 [MH] P ° 's-o 3- (1-benzenesulfonyl-4-methyl-1H-indole-2-yl) -3-oxo-propionitrile 337 [MH]
- 1254 1254
- 3-(5-fluoro-6-trifluorometil-1 H-indol -2-il)-3- oxopropionitrilo 269 [MH] 3- (5-fluoro-6-trifluoromethyl-1 H-indole -2-yl) -3- oxopropionitrile 269 [MH]
- 1255 1255
- pos-U 3-(5-metilsulfanil-1 H-indol-2-il) -3-oxopropionitrilo 231 pos-U 3- (5-methylsulfanyl-1 H-indol-2-yl) -3-oxopropionitrile 231
- 1256 1256
- h ~ 3-(6-fluoro-5-metoxi-1 H-indol-2-il) -3- oxopropionitrilo 233 h ~ 3- (6-fluoro-5-methoxy-1 H-indol-2-yl) -3- oxopropionitrile 233
- 1257 1257
- Sí? oj&yu 3-[5-benciM-(tolueno-4-sulfonil)-1H-mdol-2-N]-3- oxo-propionitrilo 429 Yes? oj & yu 3- [5-benciM- (toluene-4-sulfonyl) -1H-mdol-2-N] -3- oxo-propionitrile 429
- 1258 1258
- H ^ $CXK^ 3-(6-cloro-5-metoxi-1 H-indol-2-il) -3- oxopropionitrilo 249, 251 H ^ CXK ^ 3- (6-chloro-5-methoxy-1 H-indole-2-yl) -3-oxopropionitrile 249, 251
- 1259 1259
- “VH° f C lll 3-(5-cloro-6-metoxi-1 H-indol-2-il) -3- oxopropionitrilo 249, 251 "VH ° f C lll 3- (5-chloro-6-methoxy-1 H-indol-2-yl) -3-oxopropionitrile 249, 251
- 1260 1260
- 3-(6-isopropoxi-1H-indol-2-il)-3-oxo-propionitrilo 243 3- (6-Isopropoxy-1H-indol-2-yl) -3-oxo-propionitrile 243
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1261 1261
- 0P v'5=0 CcPL„ 1 3-(1-bencenosulfonil-4-trimetilsilaniletinil-1H-indol- 2-il) - 3-oxo-propionitrilo 421 0P v'5 = 0 CcPL „1 3- (1-benzenesulfonyl-4-trimethylsilanyletinyl-1H-indole-2-yl) - 3-oxo-propionitrile 421
- 1262 1262
- Os-q 3-[5-bromo-6-metoxi-1-(tolueno-4-sulfonil)-1H-indol- 2-il]- 3-oxo-propionitrilo 447, 449 Os-q 3- [5-bromo-6-methoxy-1- (toluene-4-sulfonyl) -1H-indole-2-yl] - 3-oxo-propionitrile 447, 449
- 1263 1263
- $ Oís,0 <XcPL„ 3-oxo-3-[5-(tolueno-4-sulfonil)-5H-[1,3] dioxolo[4,5- f]indol-6-il]-propionitrilo 383 $ Oís, 0 <XcPL „3-oxo-3- [5- (toluene-4-sulfonyl) -5H- [1,3] dioxolo [4,5- f] indole-6-yl] -propionitrile 383
- 1264 1264
- CL'-c¿ < _ 3-(6-benciloxi-1H-indol-2-il)-3-oxo-propionitrilo 291 CL'-c¿ <_ 3- (6-benzyloxy-1H-indole-2-yl) -3-oxo-propionitrile 291
- 1265 1265
- ó °So 3-[5-cidopropilmetoxi-1-(tolueno-4-sulfonil)-1H-indol- 2- il]-3-oxo-propionitrilo 409 or ° So 3- [5-cidopropylmethoxy-1- (toluene-4-sulfonyl) -1H-indole-2-yl] -3-oxo-propionitrile 409
- 1266 1266
- N r "N 3-(4-isopropoxi-1H-indol-2-il)-3-oxo-propionitrilo 243 N r "N 3- (4-isopropoxy-1H-indole-2-yl) -3-oxo-propionitrile 243
- 1267 1267
- 9 ft=£=0 QcK- 3-(1-bencenosulfonil-4-bromo-1H-indol -2-il)-3- oxo- propionitrilo 403, 405 9 ft = £ = 0 QcK- 3- (1-benzenesulfonyl-4-bromo-1H-indole -2-yl) -3- oxo-propionitrile 403, 405
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1268 1268
- / O 3-[2,2-difluoro-5-(tolueno-4-sulfonil) -5H- [1,3]]dioxolo[4,5-f]indol-6-il]-3-oxo-propionitrilo 419 / O 3- [2,2-Difluoro-5- (toluene-4-sulfonyl) -5H- [1,3]] dioxolo [4,5-f] indole-6-yl] -3-oxo-propionitrile 419
- 1269 1269
- - <s 3-[6-(3-cloro-piridin-2-il)-1 -(tol ueno-4-sulfonil)- 1H- indol-2-il]-3-oxo-propionitrilo 450, 452 - <s 3- [6- (3-Chloro-pyridin-2-yl) -1 - (toluene-4-sulfonyl) - 1 H- indol-2-yl] -3-oxo-propionitrile 450, 452
- 1270 1270
- "?*0 vXh; _h 3-[6-(3-fluoro-piridin-2-il)-1-(tolueno -4-sulfonil)- 1H- indol-2-il]-3-oxo-propionitrilo 434 "? * 0 vXh; _h 3- [6- (3-fluoro-pyridin-2-yl) -1- (toluene -4-sulfonyl) - 1H- indole-2-yl] -3-oxo-propionitrile 434
- 1271 1271
- <p x&i-, 3-[6-metil-1-(tolueno-4-sulfonil)-1H-indol-2-il]-3- oxo- propionitrilo 353 <p x & i-, 3- [6-methyl-1- (toluene-4-sulfonyl) -1H-indole-2-yl] -3- oxo-propionitrile 353
- 1272 1272
- V, ¿ XVy?* 0 3-[6-(5-fluoro-piridin-2-il)-1-(tolueno -4-sulfonil)- 1H- indol-2-il]-3-oxo-propionitrilo 434 V, XVy? * 0 3- [6- (5-fluoro-pyridin-2-yl) -1- (toluene -4-sulfonyl) - 1 H- indole-2-yl] -3-oxo-propionitrile 434
- 1273 1273
- H ^ 3-{2,3-dihidro-6H-[1,4]dioxino[2,3-f] indol-7-il)-3- oxo- propionitrilo 243 H ^ 3- {2,3-dihydro-6H- [1,4] dioxino [2,3-f] indole-7-yl) -3-oxo-propionitrile 243
- 1274 1274
- t °o ^ ^lr3^- 3-[6-(6-morfolin-4-il-piridazin-3-il) -1-(tolueno-4- sulfonil)-1 H-indol-2-il] -3-oxo-propionitrilo 502 t ° o ^ ^ lr3 ^ - 3- [6- (6-morpholin-4-yl-pyridazin-3-yl) -1- (toluene-4-sulfonyl) -1 H-indole-2-yl] -3 -oxo-propionitrile 502
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1275 1275
- <5 ‘íc&L, 3-[5-cloro-6-cidopropilmetoxi-1-(tolueno-4- sulfonil)- 1 H-indol-2-il] -3-oxo-propionitrilo 443, 445 <5 ‘íc & L, 3- [5-chloro-6-cidopropylmethoxy-1- (toluene-4- sulfonyl) - 1 H-indol-2-yl] -3-oxo-propionitrile 443, 445
- 1276 1276
- 3-(4,6-di-tert-butil-1 H-indol-2-il) -3 -oxopropionitrilo 352 3- (4,6-di-tert-butyl-1 H-indol-2-yl) -3-oxopropionitrile 352
- 1277 1277
- -Vi ^ 3-oxo-3-[1-(tolueno-4-sulfonil)-6-(5- trifluorometilpi ridin- 2-il)-1 H-indol-2-il]-propionitrilo 484 -Vi ^ 3-oxo-3- [1- (toluene-4-sulfonyl) -6- (5- trifluoromethylpi ridin- 2-yl) -1 H-indole-2-yl] -propionitrile 484
- 1278 1278
- 0 T^ctíX. 3-oxo-3-[1-(tolueno-4-sulfonil)-6-(6- trifluorometilpi ridin- 2-il)-1 H-indol-2-il]-propionitrilo 484 0 T ^ ctíX. 3-oxo-3- [1- (toluene-4-sulfonyl) -6- (6- trifluoromethylpi ridin- 2-yl) -1 H-indole-2-yl] -propionitrile 484
- 1279 1279
- V! $ TI 3-[6-(5-cloro-piridin-2-il)-1-(tolueno -4-sulfonil)- 1H- indol-2-il]-3-oxo-propionitrilo 450, 452 V! TI 3- [6- (5-chloro-pyridin-2-yl) -1- (toluene -4-sulfonyl) - 1 H- indole-2-yl] -3-oxo-propionitrile 450, 452
- 1280 1280
- tí er. J f, 3-[4,5-dibromo-1-(4-metoxi-bencil) -1H-pirrol-2-il]-3- oxo-propionitrilo 411, 413, 415 you J f, 3- [4,5-dibromo-1- (4-methoxy-benzyl) -1H-pyrrol-2-yl] -3-oxo-propionitrile 411, 413, 415
- 1281 1281
- i * 0 rV V C"XcVV 3-oxo-3-[1-(tolueno-4-sulfonil)-6-(3- trifluorometilpi ridin- 2-il)-1 H-indol-2-il]-propionitrilo 484 i * 0 rV V C "XcVV 3-oxo-3- [1- (toluene-4-sulfonyl) -6- (3- trifluoromethylpi ridin- 2-yl) -1 H-indole-2-yl] -propionitrile 484
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1282 1282
- ¥ Ó n oa?=o 3-oxo-3-[1-(tolueno-4-sulfonil)-6-(4- trifluorometilpiridin- 2-il)-1 H-indol -2-il]-propionitrilo 484 ¥ Ó n oa? = O 3-oxo-3- [1- (toluene-4-sulfonyl) -6- (4- trifluoromethylpyridin-2-yl) -1 H-indole -2-yl] -propionitrile 484
- 1283 1283
- ^y\ i? \—=H <*' *Q 3-(5-metanosulfonilo-1 H-indol-2-il) -3- oxopropionitrilo 263 ^ and \ i? \ - = H <* '* Q 3- (5-methanesulfonyl-1 H-indol-2-yl) -3-oxopropionitrile 263
- 1284 1284
- 7? 0i?-'0 3-(1-bencenosulfonil-4-isopropil-1H-indol-2-il)-3- oxo-propionitrilo 367 7? 0i? - '0 3- (1-benzenesulfonyl-4-isopropyl-1H-indole-2-yl) -3- oxo-propionitrile 367
- 1550 1550
- ci-^yJ 3-[6-cloro-1-(tolueno-4-sulfonil)-1H-indol-2-il]-3- oxo-propionitrilo 373 ci- ^ yJ 3- [6-chloro-1- (toluene-4-sulfonyl) -1H-indol-2-yl] -3- oxo-propionitrile 373
- 1551 1551
- ó ctXXr^ 3-[5-cloro-1-(tolueno-4-sulfonil)-1H-indol-2-il]-3- oxo-propionitrilo 373 or ctXXr ^ 3- [5-chloro-1- (toluene-4-sulfonyl) -1H-indole-2-yl] -3- oxo-propionitrile 373
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1552 1552
- 3-oxo-3-[1-(tolueno-4-sulfonil)-1H-indol-3-il]-propionitrilo 339 3-oxo-3- [1- (toluene-4-sulfonyl) -1H-indole-3-yl] -propionitrile 339
- 1553 1553
- O-S 0 A Ñ P qr^^*N 3-oxo-3-[1-(tolueno-4-sulfonil)-1H-indol-6-il]-propionitrilo 339 O-S 0 A Ñ P qr ^^ * N 3-oxo-3- [1- (toluene-4-sulfonyl) -1H-indole-6-yl] -propionitrile 339
- 1554 1554
- i /• f~S %to :x^N 3-[5-bromo-6-fluoro-1-(tolueno-4-sulfonil)-1H-indol- 2- il]-3-oxo-propionitrilo 435 i / • f ~ S% to: x ^ N 3- [5-bromo-6-fluoro-1- (toluene-4-sulfonyl) -1H-indole-2- yl] -3-oxo-propionitrile 435
- 1555 1555
- rS s--o Ñ O F5rX^>“U=N 3-oxo-3-[1-(tolueno-4-sulfonil)-5- trifluorometil-1 H-indol- 2-il]-propionitrilo 407 rS s - o Ñ O F5rX ^> “U = N 3-oxo-3- [1- (toluene-4-sulfonyl) -5- trifluoromethyl-1 H-indole-2-yl] -propionitrile 407
- 1556 1556
- ó %0 e Ñ 0 3-oxo-3-[1-(tolueno-4-sulfonil)-5- trifluorometoxi-1H- indol-2-il]-propionitrilo 423 or% 0 and Ñ 0 3-oxo-3- [1- (toluene-4-sulfonyl) -5- trifluoromethoxy-1H- indole-2-yl] -propionitrile 423
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1557 1557
- s-° ci'T'^rN o yo-u, Cl 3-[4,6-dicloro-1-(tolueno-4-sulfonil)-1H-indol- 2-il]-3- oxo-propionitrilo 407 s- ° ci'T '^ rN or yo-u, Cl 3- [4,6-dichloro-1- (toluene-4-sulfonyl) -1H-indole-2-yl] -3- oxo-propionitrile 407
- 1558 1558
- p S-° F 3-[6-bromo-4-fluoro-1-(tolueno-4-sulfonil)-1H-indol- 2-il]-3-oxo-propionitrilo 435 p S- ° F 3- [6-bromo-4-fluoro-1- (toluene-4-sulfonyl) -1H-indole-2-yl] -3-oxo-propionitrile 435
- 1559 1559
- , & FtF °u °'OcK_-n 3-oxo-3-[1-(tolueno-4-sulfonil)-6- trifluorometoxi-1H- indol-2-il]-propionitrilo 423 , & FtF ° u ° 'OcK_-n 3-oxo-3- [1- (toluene-4-sulfonyl) -6- trifluoromethoxy-1H- indole-2-yl] -propionitrile 423
- 1560 1560
- °Í0 3-[5,6-dicloro-1-(tolueno-4-sulfonil)-1H-indol- 2-il]-3- oxo-propionitrilo 407 ° I0 3- [5,6-dichloro-1- (toluene-4-sulfonyl) -1H-indole-2-yl] -3- oxo-propionitrile 407
- 1561 1561
- 4 s*° f^rN^ p Cl 3-[4,5-dicloro-1-(tolueno-4-sulfonil)-1H-indol- 2-il]-3- oxo-propionitrilo 407 4 s * ° f ^ rN ^ p Cl 3- [4,5-dichloro-1- (toluene-4-sulfonyl) -1H-indole-2-yl] -3- oxo-propionitrile 407
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1562 1562
- F 3-[4,6-difluoro-1-(tolueno-4-sulfonil)-1H-indol- 2-il]-3- oxo-propionitrilo 375 F 3- [4,6-Difluoro-1- (toluene-4-sulfonyl) -1H-indole-2-yl] -3- oxo-propionitrile 375
- 1563 1563
- Oc3-t*N 3-benzofurano-2-il-3-oxo-propionitrilo 186 Oc3-t * N 3-benzofuran-2-yl-3-oxo-propionitrile 186
- 1564 1564
- CÜ^N 3-benzo[b]tiofen-2-il-3-oxo-propionitrilo 202 CÜ ^ N 3-benzo [b] thiophene-2-yl-3-oxo-propionitrile 202
- 1565 1565
- 3-benzotiazol-2-il-3-oxo-propionitrilo 203 3-benzothiazol-2-yl-3-oxo-propionitrile 203
- 1566 1566
- O fjQA^n 3-(4-fluoro-fenil)-3-oxo-propionitrilo 164 O fjQA ^ n 3- (4-fluoro-phenyl) -3-oxo-propionitrile 164
- 1567 1567
- cix o 3-(3-doro-fenil)-3-oxo-propionitrilo 180 cix or 3- (3-doro-phenyl) -3-oxo-propionitrile 180
- 1568 1568
- ^ p ^ hT 3-oxo-3-quinolin-3-il-propionitrilo 197 ^ p ^ hT 3-oxo-3-quinolin-3-yl-propionitrile 197
- 1569 1569
- rN 0 (y\\^u 3-oxo-3-quinolin-7-il-propionitrilo 197 rN 0 (y \\ ^ u 3-oxo-3-quinolin-7-yl-propionitrile 197
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1570 1570
- /-v P fYv\>^n 3-oxo-3-quinoli n-6-M-propionitrilo 197 / -v P fYv \> ^ n 3-oxo-3-quinoli n-6-M-propionitrile 197
- 1571 1571
- 3-(1H-¡ndol-2-ll)-3-oxo-prop¡onitrilo 185 3- (1H-¡ndol-2-ll) -3-oxo-propitonitrile 185
Etapa 4: Síntesis del éster etílico del ácido 1-bencenosulfonil-1H-indol-2-carboxílico (1285)Stage 4: Synthesis of 1-benzenesulfonyl-1H-indole-2-carboxylic acid ethyl ester (1285)
5 Con enfriamiento en hielo, una solución en N,N-dimetilformamida (DMF) anhidra (70 mi) del éster etílico del ácido 1H-indol-2-carboxílico (45 g, 0.238 mol) se adicionó gota a gota a una solución de hidruro de sodio al 50% (13.7 g, 0.286 mol) en N,N-d¡met¡lformam¡da (DMF) anhidra (90 mi). Después de una hora y media de agitación con enfriamiento en hielo, la mezcla de reacción se calentó a temperatura ambiente, y a continuación se agitó, durante una hora. Después de enfriar en hielo, una solución en N,N-dimetilformamida (DMF) anhidra de cloruro de 10 bencenosulfonilo (50.4 g) se adicionó gota a gota, y la mezcla resultante se agitó, durante una hora. Una solución acuosa de ácido clorhídrico 0.5 N se adicionó gota a gota a la mezcla de reacción, y a continuación se le adicionó agua. La mezcla se agitó, durante 30 minutos. El sólido resultante se recolectó por filtración, y se lavó con agua y a continuación con n-hexano. El sólido se disolvió en acetato de etilo, y se lavó con una solución acuosa saturada de bicarbonato de sodio y a continuación con una solución acuosa saturada de cloruro de sodio. La capa orgánica se 15 secó sobre sulfato de sodio anhidro. El desecante se eliminó por filtración. El filtrado se concentró bajo presión reducida para dar el éster etílico del ácido 1-bencenosulfonil- 1H-indol-2-carboxíl¡co en bruto. El producto en bruto obtenido se recristalizó (acetato de etilo/hexano) para dar el éster etílico del ácido 1-bencenosulfonil- 1 H-indol-2- carboxílico (68.9 g, 79%).With ice cooling, an anhydrous N, N-dimethylformamide (DMF) solution (70 ml) of the 1H-indole-2-carboxylic acid ethyl ester (45 g, 0.238 mol) was added dropwise to a solution of 50% sodium hydride (13.7 g, 0.286 mol) in N, Nd¡met¡lformam¡da (DMF) anhydrous (90 ml). After an hour and a half of stirring with ice cooling, the reaction mixture was heated to room temperature, and then stirred, for one hour. After cooling on ice, an anhydrous N, N-dimethylformamide (DMF) solution of 10 benzenesulfonyl chloride (50.4 g) was added dropwise, and the resulting mixture was stirred, for one hour. An aqueous solution of 0.5 N hydrochloric acid was added dropwise to the reaction mixture, and then water was added. The mixture was stirred for 30 minutes. The resulting solid was collected by filtration, and washed with water and then with n-hexane. The solid was dissolved in ethyl acetate, and washed with a saturated aqueous solution of sodium bicarbonate and then with a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to give the crude 1-benzenesulfonyl-1H-indole-2-carboxylic acid ethyl ester. The crude product obtained was recrystallized (ethyl acetate / hexane) to give the 1-benzenesulfonyl-1 H-indole-2-carboxylic acid ethyl ester (68.9 g, 79%).
1H-RMN (CDCIs) 8: 8.12 (1H, d, J = 8.3 Hz), 8.04 (2H, d, J = 7.8 Hz), 7.60-7.52 (2H, m), 7.51-7.40 (3H, m), 7.31-7.21 20 (1H, m), 7.17 (1H, s), 4.40 (2H,q, J = 7.0 Hz), 1.39 (3H, t, J = 7.0 Hz)1H-NMR (CDCIs) 8: 8.12 (1H, d, J = 8.3 Hz), 8.04 (2H, d, J = 7.8 Hz), 7.60-7.52 (2H, m), 7.51-7.40 (3H, m), 7.31-7.21 20 (1H, m), 7.17 (1H, s), 4.40 (2H, q, J = 7.0 Hz), 1.39 (3H, t, J = 7.0 Hz)
ESI (LC-MS modo positivo) m/z 330 [(M+H)+]ESI (LC-MS positive mode) m / z 330 [(M + H) +]
Los compuestos de los números 1286 a 1312 enumerados en la Tabla 11, se sintetizaron mediante el mismo método como en la Etapa 4.The compounds of numbers 1286 to 1312 listed in Table 11, were synthesized by the same method as in Step 4.
Tabla 11Table 11
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1286 1286
- 9 c-s-c éster etílico del ácido 6-morfolin-4-ilmetil-1- (bencenosulfonil)-1 H-indol- 2-carboxílico 429 9 c-s-c 6-morpholin-4-ylmethyl-1- (benzenesulfonyl) -1 H-indole-2-carboxylic acid ethyl ester 429
- 1287 1287
- P o=&=c éster etílico del ácido 5-morfolin-4-ilmetil-1- (bencenosulfonil)-1 H-indol- 2-carboxílico 429 P o = & = c 5-morpholin-4-ylmethyl-1- (benzenesulfonyl) -1 H-indole-2-carboxylic acid ethyl ester 429
- 1288 1288
- 9 Qrj^ Q éster etílico del ácido 1-bencenosulfonil-4-morfolin-4-il-1H- indol-2- carboxílico 415 9 Qrj ^ Q 1-benzenesulfonyl-4-morpholin-4-yl-1H-indole-2-carboxylic acid ethyl ester 415
- 1289 1289
- 5oü oi-v o éster etílico del ácido 1-bencenosulfonil-4-morfolin-4-ilmetil- 1 H-indol- 2-carboxílico 429 5oü oi-v or 1-benzenesulfonyl-4-morpholin-4-ylmethyl- 1 H-indole-2-carboxylic acid ethyl ester 429
- 1290 1290
- 9 0=5=0 r éster etílico del ácido 1-bencenosulfonil-4-fluoro-1H-indol- 2-carboxílico 348 9 0 = 5 = 0 r 1-benzenesulfonyl-4-fluoro-1H-indole-2-carboxylic acid ethyl ester 348
- 1291 1291
- (5 o 4 o ,£XK-n éster etílico del ácido 1-bencenosulfonil-5-fluoro-1H-indol- 2-carboxílico 348 (5 or 4 o, XK-n 1-benzenesulfonyl-5-fluoro-1H-indole-2-carboxylic acid ethyl ester 348
- 1292 1292
- 9 OSO fXl>V. éster etílico del ácido 1-bencenosulfonil-6-fluoro-1H-indol - 2-carboxílico 348 9 BEAR fXl> V. 1-Benzenesulfonyl-6-fluoro-1H-indole-2-carboxylic acid ethyl ester 348
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1293 1293
- 9 o^s-o 2 éster etílico del ácido 1-bencenosulfonil-1H-pirrolo[2,3-b] piridina-2- carboxílico 331 9 o ^ s-o 2 1-benzenesulfonyl-1H-pyrrolo [2,3-b] pyridine-2-carboxylic acid ethyl ester 331
- 1294 1294
- °$°o o—x éster etílico del ácido 1-bencenosulfonil-1H-pirrolo [3,2- c]piridina-2- carboxílico 331 1 ° or o-x 1-benzenesulfonyl-1 H -pyrrolo [3,2- c] pyridine-2-carboxylic acid ethyl ester 331
- 1295 1295
- 5o. éster etílico del ácido 1-bencenosulfonil-5-fluoro-6- morfolin-4-ilmetil- 1 H-indol -2-carboxílico 447 5th. 1-Benzenesulfonyl-5-fluoro-6- morpholin-4-ylmethyl-1 H-indole-2-carboxylic acid ethyl ester 447
- 1296 1296
- p cr*XXH éster metílico del ácido 1-bencenosulfonil-6-(2-morfolin - 4-il-etoxi)-1 H-indol- 2-carboxílico 445 p cr * XXH 1-benzenesulfonyl-6- (2-morpholin-4-yl-ethoxy) -1 H-indole-2-carboxylic acid methyl ester 445
- 1297 1297
- r\ PX sTOH éster metílico del ácido 1-bencenosulfonil-6-(tetrahidro- piran-4-iloxi)-1 H-indol- 2-carboxílico 416 r \ PX sTOH 1-benzenesulfonyl-6- (tetrahydropyran-4-yloxy) -1 H-indole-2-carboxylic acid methyl ester 416
- 1298 1298
- O 4-cloro-1-(tolueno-4-sulfonil) -1 H-indol 306, 308 O 4-chloro-1- (toluene-4-sulfonyl) -1 H-indole 306, 308
- 1299 1299
- $ 0*0 F "xJ DA éster etílico del ácido 5-((R)-3-fluoro-pirrolidin-1-ilmetil)-1- (tolueno-4- sulfonil) -1 H-indol-2-carboxílico 445 $ 0 * 0 F "xJ DA 5 - ((R) -3-Fluoro-pyrrolidin-1-ylmethyl) -1- (toluene-4-sulfonyl) -1 H-indole-2-carboxylic acid ethyl ester 445
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1300 1300
- { 0 o*/ S[ ?**} XíX / \ éster etílico del ácido 6-bromo-1-(tolueno-4-sulfonil) -1H- indol-2- carboxílico 422, 424 {0 or * / S [? **} Xix / 6-bromo-1- (toluene-4-sulfonyl) -1H- indole-2-carboxylic acid ethyl ester 422, 424
- 1301 1301
- 9 o=s=o éster etílico del ácido 5-bromo-1-(tolueno-4-sulfonil) -1H- indol-2- carboxílico 422,424 9 o = s = o 5-Bromo-1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid ethyl ester 422,424
- 1302 1302
- 9 o--\ i éster etílico del ácido 1-bencenosulfonil-4-yodo-1H-indol-2- carboxílico 456 9 or - \ 1-benzenesulfonyl-4-iodo-1H-indole-2-carboxylic acid ethyl ester 456
- 1303 1303
- | 0=S-0 00^0- éster metílico del ácido 6-isopropil-1-(tolueno-4-sulfonil) -1H- indol-2- carboxílico 372 | 0 = S-0 00 ^ 0- 6-Isopropyl-1- (toluene-4-sulfonyl) -1H- indole-2-carboxylic acid methyl ester 372
- 1304 1304
- ó cB^U éster etílico del ácido 1-(tolueno-4-sulfonil)-1H-pirrolo [3,2- b]piridina-2- carboxílico 345 or cB ^ U 1- (toluene-4-sulfonyl) -1H-pyrrolo [3,2- b] pyridine-2-carboxylic acid ethyl ester 345
- 1305 1305
- [ u éster metílico del ácido 6-metilsulfanil-1-(tolueno-4-sulfonil)- 1 H-indol-2- carboxílico 376 [u 6-Methylsulfanyl-1- (toluene-4-sulfonyl) -1 H-indole-2-carboxylic acid methyl ester 376
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1306 1306
- P °:S O éster metílico del ácido 4-metil-1-(tolueno-4-sulfonil) -1H- indol-2- carboxílico 344 P °: S O 4-methyl-1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid methyl ester 344
- 1307 1307
- i? 0=5-0 1 0 éster metílico del ácido 5-(tolueno-4-sulfonil)-5H-[1,3] dioxolo[4,5-f]indol-6- carboxílico 374 i? 0 = 5-0 1 0 5- (Toluene-4-sulfonyl) -5H- [1,3] dioxolo [4,5-f] indole-6- carboxylic acid methyl ester 374
- 1308 1308
- Q 0=S 0 QcPU Br éster etílico del ácido 1-bencenosulfonil-4-bromo-1H-indol- 2-carboxílico 408,410 Q 0 = S 0 QcPU Br 1-benzenesulfonyl-4-bromo-1H-indole-2-carboxylic acid ethyl ester 408,410
- 1309 1309
- <¡> Ü=S=0 1 'TXK- éster metílico del ácido 6-metil-1-(tolueno-4-sulfonil) -1H- indol-2- carboxílico 344 <¡> Ü = S = 0 1 'TXK- 6-methyl-1- (toluene-4-sulfonyl) -1H- indole-2-carboxylic acid methyl ester 344
- 1310 1310
- L° P Br éster etílico del ácido 4-bromo-1-(tolueno-4-sulfonil)-1H- pirrol-2-carboxílico 372,374 L ° P 4-Bromo-1- (toluene-4-sulfonyl) -1H-pyrrole-2-carboxylic acid ethyl ester 372,374
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1311 1311
- ° s=\ O > éster etílico del ácido 1-(tolueno-4-sulfonil)-1 H-pirrol -2- carboxílico 294 ° s = \ O> 1- (toluene-4-sulfonyl) -1 H-pyrrole -2-carboxylic acid ethyl ester 294
- 1312 1312
- 9 0=S=O (jck-. éster etílico del ácido 1-bencenosulfonil-4-isopropil-1H-indol-2- carboxílico 372 9 0 = S = O (jck-. 1-benzenesulfonyl-4-isopropyl-1H-indole-2-carboxylic acid ethyl ester 372
Etapa 5: Síntesis de [5-am¡no-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-[4-(2-metox¡-et¡lam¡no)-1-(toluene-4- sulfonil)-1 H-indol-2-¡l]-metanona (1313)Stage 5: Synthesis of [5-amine-1- (2-methyl-1H-benzyldazol-5-l) -1H-p¡razol-4-l] - [4- (2 -methox¡-et¡lam¡no) -1- (toluene-4-sulfonyl) -1 H-indole-2-¡l] -methanone (1313)
Se disolvieron yoduro de cobre (I) (16 mg, 0.086 mmol), L-prolina (37 mg, 0.32 mmol), y [5-amino-1-(2-metil-1H- bencimidazol-5-il)-1H-pirazol-4-il]-[6-yodo-1-(tolueno-4-sulfonil)-1 H-indol-2-il]-metanona (104 mg) en dimetilsulfóxido (DMSO) anhidro, y a continuación se le adicionaron 1,8-diazabiciclo[5.4.0]undec-7-eno (49 pl) y 2-metoxietilamina (43 pl). La mezcla se calentó a 80°C con agitación bajo una atmósfera de nitrógeno, durante 18 horas. Después la 10 mezcla de reacción se enfrió a temperatura ambiente, se le adicionó agua de amoníaco al 25%. La mezcla resultante se extrajo con acetato de etilo. La capa orgánica se aisló, se lavó con una solución acuosa de ácido clorhídrico 1 M y a continuación con una solución acuosa saturada de cloruro de sodio, y se secó sobre sulfato de magnesio anhidro. Después el desecante se eliminó por filtración, el solvente se separó por destilación bajo presión reducida. El residuo resultante se purificó por cromatografía (dlclorometano/metanol = 100/5) utilizando una pequeña 15 cantidad de síllca gel para dar el producto en bruto de [5-amlno-1-(2-metil-1H-bencim¡dazol-5-ll)-1H-p¡razol-4-¡l]-[4-(2- metox¡-et¡lamlno)-1-(tolueno-4-sulfon¡l)-1H-¡ndol- 2-il]-metanona. El producto en bruto obtenido se utilizó en reacciones posteriores sin purificación.Copper (I) iodide (16 mg, 0.086 mmol), L-proline (37 mg, 0.32 mmol), and [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H were dissolved -pyrazol-4-yl] - [6-iodo-1- (toluene-4-sulfonyl) -1 H-indol-2-yl] -methanone (104 mg) in anhydrous dimethylsulfoxide (DMSO), and then added 1,8-diazabicyclo [5.4.0] undec-7-ene (49 pl) and 2-methoxyethylamine (43 pl). The mixture was heated at 80 ° C with stirring under a nitrogen atmosphere, for 18 hours. After the reaction mixture was cooled to room temperature, 25% ammonia water was added. The resulting mixture was extracted with ethyl acetate. The organic layer was isolated, washed with a 1 M aqueous hydrochloric acid solution and then with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. After the desiccant was removed by filtration, the solvent was distilled off under reduced pressure. The resulting residue was purified by chromatography (dichloromethane / methanol = 100/5) using a small amount of silica gel to give the crude product of [5-aml-1- (2-methyl-1H-benzimdazol-5 -ll) -1H-p¡razol-4-¡l] - [4- (2- metox¡-et¡lamlno) -1- (toluene-4-sulfon¡l) -1H-¡ndol- 2-il ] -metanone. The crude product obtained was used in subsequent reactions without purification.
ESI (LC-MS modo positivo) m/z 584 [(M+H)+]ESI (LC-MS positive mode) m / z 584 [(M + H) +]
Los compuestos de los números 1314 a 1320 enumerados en la Tabla 12, se sintetizaron mediante el mismo 20 método como en la Etapa 5.The compounds of Nos. 1314 to 1320 listed in Table 12, were synthesized by the same method as in Step 5.
Tabla 12Table 12
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1314 1314
- 4 O [5-amino-1-(2-metil-1H-bencimidazol -5-il)- 1 Hpirazol- 4-il]-[4-(2-morfolin-4-il-etilamino)- 1- (tolueno-4-sulfonil)-1 H-indol-2-il] -metanona 639 4 O [5-amino-1- (2-methyl-1H-benzimidazol -5-yl) -1 Hpirazol-4-yl] - [4- (2-morpholin-4-yl-ethylamino) -1- (toluene -4-sulfonyl) -1 H-indole-2-yl] -methanone 639
- 1315 1315
- § H 0¿S=0 [5-amino-1-(2-metil-1H-bencimidazol -5-il)- 1 Hpirazol- 4-il]-[6-(2-morfolin-4-il-etilamino)- 1- (tolueno-4-sulfonil)-1 H-indol-2-il] -metanona 639 § H 0¿S = 0 [5-amino-1- (2-methyl-1H-benzimidazol -5-yl) - 1 Hpirazol-4-yl] - [6- (2-morpholin-4-yl-ethylamino) - 1- (toluene-4-sulfonyl) -1 H-indol-2-yl] -methanone 639
- 1316 1316
- (> [5-amino-1-(2-metil-1H-bencimidazol -5-il)- 1Hpirazol- 4-il]-[4-(2-metoxi -etilamino)- 1- (tolueno-4-sulfonil) -1 H-indol-2-il]-metanona 584 (> [5-amino-1- (2-methyl-1H-benzimidazol -5-yl) -1Hpyrazol-4-yl] - [4- (2-methoxy-ethylamino) -1- (toluene-4-sulfonyl) -1 H-indole-2-yl] -methanone 584
- 1317 1317
- 4 c * ?*V [5-amino-1-(2-metil-1H-bencimidazol-5-il)- 1Hpirazol- 4-il] -[4-(2-hidroxi-1- hidroximetiletilamino)- 1-(tolueno-4-sulfonil) - 1 H-indol-2-il]-metanona 600 4 c *? * V [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) - 1 Hpirazol-4-yl] - [4- (2-hydroxy-1- hydroxymethylethylamino) - 1- ( toluene-4-sulfonyl) - 1 H-indol-2-yl] -methanone 600
- 1318 1318
- 4» 0-3^ or-'KW ^ [5-amino-1-(2-metil-1H-bencimidazol -5-il)- 1Hpirazol- 4-il]- [4-(2-piridin -4-il-etilamino)- 1- (tolueno-4-sulfonil)-1H-indol-2-il]-metanona 631 4 »0-3 ^ or-'KW ^ [5-amino-1- (2-methyl-1H-benzimidazol -5-yl) - 1Hpyrazol- 4-yl] - [4- (2-pyridin -4-yl -ethylamino) - 1- (toluene-4-sulfonyl) -1H-indole-2-yl] -methanone 631
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1319 1319
- $ 0=3=0. [5-amino-1-(2-metil-1H-bencimidazol -5-il)-1 Hpirazol- 4-il]-[6-morfolin -4-M-1 -(tolueno-4- sulfonil)-1 H-indol - 2-¡l]-metanona 596 $ 0 = 3 = 0. [5-amino-1- (2-methyl-1H-benzimidazol -5-yl) -1 Hpirazol-4-yl] - [6-morpholin-4-M-1 - (toluene-4-sulfonyl) -1 H -indole - 2-¡l] -methanone 596
- 1320 1320
- 9. 0 éster etílico del ácido 1-bencenosulfonil-4-morfolin-4- ¡1-1 H-indol-2- carboxílico 415 9. 0 1-Benzenesulfonyl-4-morpholin-4-1, 1-1H-indole-2-carboxylic acid ethyl ester 415
Etapa 6: Síntesis de la [5-amino-1-(2-metil-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-il]-[5-(morfolina-4-carbon¡l)-1-(tolueno-Step 6: Synthesis of [5-amino-1- (2-methyl-1H-benzyldazol-5-yl) -1H-pyrazol-4-yl] - [5- (morpholine-4-carbon) l) -1- (toluene-
4-sulfonil)-1 H-índol-2-M] metanona (1321)4-sulfonyl) -1 H-indol-2-M] methanone (1321)
El ácido 2-[5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-carbon¡l]-1-(tolueno-4-sulfon¡l)-1H-¡ndol-5- carboxílico (113 mg) se disolvió en agua (5 mi) y tetrahidrofurano (THF) (10 mi), y a continuación, se le adicionaron morfolina (53.5 pl) y N-(3-dimetilaminopropil)-N’-etilcarbodiimida clorhidrato (WSC-HCI) (43 mg). La mezcla se agitó a temperatura ambiente, durante 24 horas. A continuación, la mezcla de reacción se concentró bajo presión 10 reducida. El residuo resultante se purificó por cromatografía de columna de sílica gel (metanol/diclorometano = 0/100 a 17/100) para dar la [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[5-(morfolina-4-carbonil)-1-(tolueno- 4- sulfon¡l)-1H-indol-2-il]-metanona (59 mg).2- [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-carbonyl] -1- (toluene-4-sulfonyl) -1H- Ndol-5- carboxylic acid (113 mg) was dissolved in water (5 ml) and tetrahydrofuran (THF) (10 ml), and then morpholine (53.5 pl) and N- (3-dimethylaminopropyl) -N 'were added -ethylcarbodiimide hydrochloride (WSC-HCI) (43 mg). The mixture was stirred at room temperature for 24 hours. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol / dichloromethane = 0/100 to 17/100) to give [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H -pyrazol-4-yl] - [5- (morpholine-4-carbonyl) -1- (toluene-4-sulfonl) -1H-indole-2-yl] -methanone (59 mg).
1H-RMN (DMSO-D6) 8: 12.49 (1.0H, d, J = 9.3 Hz), 8.08 (3.0H, m), 7.82-7.74 (2.0H, m), 7.70-7.64 (1.0H, m), 7.58 (1 .OH, d, J = 8.3 Hz), 7.53-7.42 (3.0H, m), 7.35-7.25 (2.0H, m), 7.13-6.89 (2.0H, m), 3.69-3.51 (4.0H, m), 3.40-3.28 15 (4.OH, m), 2.54 (3.0H, s), 2.38 (3.0H, s) ESI (LC-MS modo positivo) m/z 624 [(M+H)+]1H-NMR (DMSO-D6) 8: 12.49 (1.0H, d, J = 9.3 Hz), 8.08 (3.0H, m), 7.82-7.74 (2.0H, m), 7.70-7.64 (1.0H, m) , 7.58 (1 .OH, d, J = 8.3 Hz), 7.53-7.42 (3.0H, m), 7.35-7.25 (2.0H, m), 7.13-6.89 (2.0H, m), 3.69-3.51 (4.0 H, m), 3.40-3.28 15 (4.OH, m), 2.54 (3.0H, s), 2.38 (3.0H, s) ESI (LC-MS positive mode) m / z 624 [(M + H) +]
Los compuestos de los números 1322 a 1326, 1572 a 1579 enumerados en la Tabla 13, se sintetizaron mediante el mismo método como en la Etapa 6.The compounds of Nos. 1322 to 1326, 1572 to 1579 listed in Table 13, were synthesized by the same method as in Step 6.
Tabla 13Table 13
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1322 1322
- C-S=G [5-amino-1-(2-metil-1H-bencimidazol-5-il)- 1Hpirazol- 4-il] -[5-(4-metilpiperadina-1-carbonil) - 1-(tolueno-4-sulfonil)-1H-indol-2-il]-metanona 637 CS = G [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpirazol-4-yl] - [5- (4-methylpiperadine-1-carbonyl) -1- (toluene-4 -sulfonyl) -1H-indole-2-yl] -methanone 637
- 1323 1323
- [5-amino-1-(2-metil-1H-bencimidazol-5-il)- 1Hpirazol- 4-il] -[5-(piperadina-1-carbonil)-1- (tolueno- 4-sulfonil)-1 H-indol-2-il] -metanona 623 [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpyrazol-4-yl] - [5- (piperadine-1-carbonyl) -1- (toluene-4-sulfonyl) -1 H-indole-2-yl] -methanone 623
- 1324 1324
- F [5-amino-1-(2-metil-1H-bencimidazol-5-il)- 1Hpirazol- 4-il] -[5-(4,4-difluoro-piperidina-1- carbonil)- 1-(tolueno-4-sulfonil) -1 H-indol-2-il]- metanona 658 F [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpirazol-4-yl] - [5- (4,4-difluoro-piperidine-1- carbonyl) -1- (toluene -4-sulfonyl) -1 H-indole-2-yl] - methanone 658
- 1325 1325
- F F O-S-O^ rS ^ N'WH [5-amino-1-(2-metil-1H-bencimidazol-5-il)- 1Hpirazol- 4-il] -[5-(3,3-difluoro-piperidina-1- carbonil)- 1-(tolueno-4-sulfonil) -1 H-indol-2-il]- metanona 658 FF OSO ^ rS ^ N'WH [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hyrazol-4-yl] - [5- (3,3-difluoro-piperidine-1- carbonyl) - 1- (toluene-4-sulfonyl) -1 H-indole-2-yl] - methanone 658
- 1326 1326
- (2,2,2-trifluoro-etil)-amida del ácido [5-amino-1-(2- metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4-carbonil]- 1-(tolueno-4-sulfonil) -1 H-indol- 5-carboxílico 636 [5-Amino-1- (2- methyl-1 H-benzimidazol-5-yl) -1-pyrazol-4-carbonyl] -1- (toluene-) (2,2,2-trifluoro-ethyl) -amide 4-sulfonyl) -1 H-indole-5-carboxylic 636
- 1572 1572
- Ó f r V¡F tvox^- ° v"'OCr H [5-amino-1-(2-metil-1H-bencimidazol-5-il)- 1Hpirazol- 4-il]-[5-(3,3-difluoro-pirrolidina-1- carbonil)-1-(tolueno-4-sulfonil)-1 H-indol-2-il]- metanona 644 Ó fr V¡F tvox ^ - ° v "'OCr H [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) - 1 Hpirazol-4-yl] - [5- (3,3- difluoro-pyrrolidine-1- carbonyl) -1- (toluene-4-sulfonyl) -1 H-indole-2-yl] - methanone 644
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1573 1573
- d o £0 1 É50 L“- 0 cXO' [5-amino-1-(2-metil-1H-bencimidazol-5-il)- 1 Hpirazol- 4-il]-[5-(2,6-dimetil-morfolina-4- carbonil)-1-(tolueno-4-sulfonil)-1 H-indol-2-il]- metanona 652 do £ 0 1 É50 L "- 0 cXO '[5-amino-1- (2-methyl-1H-benzimidazol-5-yl) - 1 Hpirazol-4-yl] - [5- (2,6-dimethyl- morpholine-4- carbonyl) -1- (toluene-4-sulfonyl) -1 H-indol-2-yl] - methanone 652
- 1574 1574
- 0 o UyÍXM ^ ¿ V^W- ^"h [5-amino-1-(2-metil-1H-bencimidazol-5-il)- 1Hpirazol- 4-il]-[5-([1,4']bipiperidinil-1 '-carbonil)- 1- (tolueno-4-sulfonil)-1H-indol-2-il]-metanona 705 0 or UyXM ^ ¿V ^ W- ^ "h [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) - 1Hpirazol-4-yl] - [5 - ([1,4 '] bipiperidinyl-1 '-carbonyl) - 1- (toluene-4-sulfonyl) -1H-indole-2-yl] -methanone 705
- 1575 1575
- P 0 FvL-F X j XVOH-'”' ’ vitfr [5-amino-1-(2-metil-1H-bencimidazol-5-il)- 1Hpirazol- 4-il]-{1-(tolueno-4-sulfonil)-5-[4-(2,2,2- trifluoro-etil)-piperazina-1 -carbonil]-1 H-indol- 2-il}- metanona 705 P 0 FvL-F X j XVOH- '”' 'vitfr [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) - 1 Hpirazol-4-yl] - {1- (toluene-4- sulfonyl) -5- [4- (2,2,2- trifluoro-ethyl) -piperazine-1-carbonyl] -1 H-indole-2-yl} - methanone 705
- 1576 1576
- d QyjO&i^ ° iV [5-amino-1-(2-metil-1H-bencimidazol-5-il)- 1Hpirazol- 4-il]-[5-[4-(2-hidroxi-etil)-piperazina- 1- carbonil]-1-(tolueno-4-sulfonil)-1 H-indol-2-il]- metanona 667 d QyjO & i ^ ° iV [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) - 1Hpyrazol- 4-yl] - [5- [4- (2-hydroxy-ethyl) -piperazine- 1 - carbonyl] -1- (toluene-4-sulfonyl) -1 H-indole-2-yl] - methanone 667
- 1577 1577
- d „ F V® * %r [5-amino-1-(2-metil-1H-bencimidazol-5-il)- 1Hpirazol- 4-il]-[5-(3,3,4,4-tetrafluoro-pirrolidina-1- carbonil)-1-(tolueno-4-sulfonil)-1 H-indol-2-il]- metanona 680 d „FV® *% r [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) - 1 Hpirazol-4-yl] - [5- (3,3,4,4-tetrafluoro-pyrrolidine -1- carbonyl) -1- (toluene-4-sulfonyl) -1 H-indole-2-yl] - methanone 680
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1578 1578
- F OkXX^w"*- [5-amino-1-(2-metil-1H-bencimidazol-5-il)- IHpirazol- 4-i l]-[5-(( R)-3-fl uoro-pi rrolidina-1 - carbonil)-1-(tolueno-4-sulfonil)-1H-indol-2-il]- metanona 626 F OkXX ^ w "* - [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) - IHpirazol-4-yl] - [5 - ((R) -3-fl uoro-pi rrolidine -1 - carbonyl) -1- (toluene-4-sulfonyl) -1H-indole-2-yl] - methanone 626
- 1579 1579
- buoá-O* VyyV v H [5-amino-1-(2-metil-1H-bencimidazol-5-il)- IHpirazol- 4-¡l]-[5-((S)-3-fluoro-pi rrolidina-1 - carbonil)-1-(tolueno-4-sulfonil)-1 H-indol-2-il]- metanona 626 buoá-O * VyyV v H [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) - I-pyrazol-4-yl] - [5 - ((S) -3-fluoro-pi rrolidine -1 - carbonyl) -1- (toluene-4-sulfonyl) -1 H-indole-2-yl] - methanone 626
Etapa 7: Síntesis de 2-[5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-carbon¡l]-1-(tolueno-4-sulfonil) -1H- indol-6-carbaldehido (1327)Step 7: Synthesis of 2- [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-carbonyl] -1- (toluene-4-sulfonyl) -1H - indole-6-carbaldehyde (1327)
En un recipiente a prueba de presión, se disolvieron acetato de paladio (1.0 mg, 0.0044 mmol), 1,3-bis(difenilfosfino) propano (1.8 mg, 0.0044 mmol), [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-yodo-1-(tolueno-4- sulfonil)-1 H-indol- 2-il]-metanona (100 mg, 0.16 mmol), y carbonato de sodio (18 mg, 0.17 mmol) en N,N- dimetilformamida (DMF) anhidra (0.22 mi). Después se adicionó trietilsilano (52 jxl, 0.33 mmol), el aire dentro delIn a pressure-proof vessel, palladium acetate (1.0 mg, 0.0044 mmol), 1,3-bis (diphenylphosphino) propane (1.8 mg, 0.0044 mmol), [5-amino-1- (2-methyl-) were dissolved 1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6-iodo-1- (toluene-4-sulfonyl) -1 H-indole-2-yl] -methanone (100 mg, 0.16 mmol ), and sodium carbonate (18 mg, 0.17 mmol) in anhydrous N, N-dimethylformamide (DMF) (0.22 ml). Then triethylsilane (52 jxl, 0.33 mmol) was added, the air inside the
10 recipiente se reemplazó con monóxido de carbono. A continuación, la mezcla de reacción se calentó a 60°C con agitación bajo presión con monóxido de carbono (3 atm), durante 24 horas. Después la mezcla de reacción se enfrió a temperatura ambiente, la presión se liberó a presión ambiental. La mezcla de reacción se diluyó con acetato de etilo. El carbonato de sodio se eliminó por filtración. El filtrado se concentró bajo presión reducida. El residuo resultante se purificó por cromatografía de columna de sílica gel (diclorometano/metanol = 100/5) para dar el 2-[5-10 vessel was replaced with carbon monoxide. Then, the reaction mixture was heated at 60 ° C with stirring under pressure with carbon monoxide (3 atm), for 24 hours. After the reaction mixture was cooled to room temperature, the pressure was released at ambient pressure. The reaction mixture was diluted with ethyl acetate. Sodium carbonate was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol = 100/5) to give 2- [5-
15 amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-carbonil]-1-(tolueno-4-sulfonil) -1H-¡ndol-6-carbaldehido como un sólido de color amarillo (80 mg, 85%).Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-carbonyl] -1- (toluene-4-sulfonyl) -1H-¡-dol-6-carbaldehyde as a solid of yellow color (80 mg, 85%).
1H-RMN (CDCI3) 8: 10.14 (1 .OH, s), 9.81-9.40 (1 OH, brm), 8.61 (1 .OH, d, J = 3.9 Hz), 8.09 (2.0H, d, J = 7.3 Hz), 7.86-7.72 (4.OH, m), 7.52-7.30 (4.0H, m), 7.02 (1 .OH, s), 6.07 (1 .OH, brs), 6.04 (1 .OH, brs), 2.67 (3.0H, s), 2.40 (3.0H, s)1 H-NMR (CDCI3) 8: 10.14 (1 .OH, s), 9.81-9.40 (1 OH, brm), 8.61 (1 .OH, d, J = 3.9 Hz), 8.09 (2.0H, d, J = 7.3 Hz), 7.86-7.72 (4.OH, m), 7.52-7.30 (4.0H, m), 7.02 (1 .OH, s), 6.07 (1 .OH, brs), 6.04 (1 .OH, brs ), 2.67 (3.0H, s), 2.40 (3.0H, s)
20 ESI (LC-MS modo positivo) m/z 539 [(M+H)+]20 ESI (LC-MS positive mode) m / z 539 [(M + H) +]
Síntesis de 2-[5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-carbonil]-1-(tolueno-4-sulfonil) -1 H-indol-5- carbaldehido (1328)Synthesis of 2- [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-carbonyl] -1- (toluene-4-sulfonyl) -1 H-indole-5 - carbaldehyde (1328)
2-[5-Amino-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-carbon¡l]-1-(tolueno-4-sulfon¡l)-1H-¡ndol-5- carbaldehldo se sintetizó por el mismo método como en la Etapa 7.2- [5-Amino-1- (2-methyl-1H-benzyldazol-5-l) -1 H -pyrazol-4-carbon] -1- (toluene-4- sulfon¡l) -1H-¡ndol-5- carbaldehldo was synthesized by the same method as in Step 7.
ESI (LC-MS modo positivo) m/z 539 [(M+H)+]ESI (LC-MS positive mode) m / z 539 [(M + H) +]
5 Etapa 8: Síntesis de 2-[5-amino-1-(2-metil-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-carbonil]-1H-indol-6-carbaldehido (1329)5 Step 8: Synthesis of 2- [5-amino-1- (2-methyl-1H-benzyldazol-5-yl) -1H-pyrazol-4-carbonyl] -1H-indole-6-carbaldehyde ( 1329)
Se disolvieron el 2-[5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-carbonil]-1-(tolueno-4-sulfonil)-1H-indol-6- carbaldehído (29 mg, 0.054 mmol), 1-metilpiperazina (7 jxl, 0.066 mmol), y triacetoxiborohidruro de sodio (17 mg, 10 0.083 mmol) en diclorometano anhidro (0.5 mi) y se agitó a temperatura ambiente bajo una atmósfera de nitrógeno,2- [5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-carbonyl] -1- (toluene-4-sulfonyl) -1H-indole-6 - carbaldehyde (29 mg, 0.054 mmol), 1-methylpiperazine (7 jxl, 0.066 mmol), and sodium triacetoxyborohydride (17 mg, 10 0.083 mmol) in anhydrous dichloromethane (0.5 ml) and stirred at room temperature under an atmosphere of nitrogen,
durante 14 horas. Se adicionó una solución acuosa saturada de bicarbonato de sodio a la mezcla de reacción. A continuación, la mezcla se extrajo con acetato de etilo. La capa orgánica se aisló, se lavó con una solución acuosa saturada de cloruro de sodio, y se secó sobre sulfato de magnesio anhidro. El desecante se eliminó por filtración. El filtrado se concentró bajo presión reducida. El residuo resultante se purificó por cromatografía de columna de síllca 15 gel (diclorometano/metanol = 100/15) para dar la [5-amino-1-(2-metil-1H-bencimidazol-5-¡l)-1H-p¡razol-4-¡l]-[6-(4- metil-piperazin-1 -ilmetil)-1 -(tolueno-4-sulfonil)- 1H-indol-2-il]-metanona como un sólido de color amarillo (29 mg, 86%).for 14 hours A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture. Then, the mixture was extracted with ethyl acetate. The organic layer was isolated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol = 100/15) to give [5-amino-1- (2-methyl-1H-benzimidazol-5-l) -1H-p Razol-4-¡l] - [6- (4- methyl-piperazin-1-methylmethyl) -1 - (toluene-4-sulfonyl) - 1H-indole-2-yl] -methanone as a yellow solid (29 mg, 86%).
ESI (LC-MS modo positivo) m/z 623 [(M+H)+]ESI (LC-MS positive mode) m / z 623 [(M + H) +]
Los compuestos de los números 1330 a 1358 enumerados en la Tabla 14, se sintetizaron mediante el mismo 20 método como en la Etapa 8.The compounds of numbers 1330 to 1358 listed in Table 14, were synthesized by the same method as in Step 8.
Tabla 14Table 14
- Compuesto Compound
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- No. Do not.
- 1330 1330
- O XnK, éster etílico del ácido 6-morfolin-4-ilmetil-1-(tolueno-4- sulfonil)-1 H-indol- 2-carboxílico 443 O XnK, 6-morpholin-4-ylmethyl-1- (toluene-4-sulfonyl) -1 H-indol-2-carboxylic acid ethyl ester 443
- 1331 1331
- °í¡! QjOH^ éster etílico del ácido 5-morfolin-4-ilmetil-1- bencenosulfonil-1 H-indol- 2-carboxílico 429 ° í¡! QjOH ^ 5-morpholin-4-ylmethyl-1- benzenesulfonyl-1 H-indole-2-carboxylic acid ethyl ester 429
- 1332 1332
- O Ho o éster etílico del ácido 1-bencenosulfonil-4-morfolin-4- ilmetil- 1 H-indol- 2-carboxílico 429 O Ho or 1-benzenesulfonyl-4-morpholin-4-ylmethyl-1 H-indole-2-carboxylic acid ethyl ester 429
- 1333 1333
- -CU7RV éster etílico del ácido 5-((R)-3-fluoro-pirrolidin-1-ilmetil)-1- (tolueno-4- sulfonil) -1 H-indol-2-carboxílico 445 -CU7RV 5 - ((R) -3-fluoro-pyrrolidin-1-ylmethyl) -1- (toluene-4-sulfonyl) -1 H-indole-2-carboxylic acid ethyl ester 445
- 1334 1334
- Ó "0COK, éster etílico del ácido 6-fluoro-5-(4-metil-piperazin-1- ilmetil)-1 -(tolueno- 4-sulfonil) -1H-indol-2-carboxílico 474 Ó "0COK, 6-fluoro-5- (4-methyl-piperazin-1- ylmethyl) -1 - (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid ethyl ester 474
- 1335 1335
- °$o cCOH^ éster etílico del ácido 6-fluoro-5-pirrolidin-1 -ilmetil-1- (tolueno-4-sulfonil)- 1 H-indol-2-carboxílico 445 ° 0 or cCOH ^ 6-fluoro-5-pyrrolidin-1-ylmethyl-1- (toluene-4-sulfonyl) - 1 H-indole-2-carboxylic acid ethyl ester 445
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1336 1336
- 9 opeo 1-bencenosulfonil-5-fluoro-6-morfolin-4-ilmetil- 1 H-i ndol 375 9 opeo 1-benzenesulfonyl-5-fluoro-6-morpholin-4-ylmethyl- 1 H-i ndol 375
- 1337 1337
- „ p tert-butil éster del ácido 4-(1-bencenosulfonil-1H-indol-5- ilmetil)-piperadin- 1-carboxílico 456 „P tert-Butyl ester of 4- (1-benzenesulfonyl-1H-indol-5- ylmethyl) -piperadin-1-carboxylic acid 456
- 1338 1338
- yOXO-L*' r ~'X£r 1-{4-[2-[5-amino-1-(2-metil-1H-bencimidazol-5-il)- 1H- pirazol-4-carbonil] -1-(tolueno-4-sulfonil) -1 H-indol- 6- ilmetil]-piperazin -1-il}-etanona 651 yOXO-L * 'r ~' X £ r 1- {4- [2- [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) - 1 H- pyrazol-4-carbonyl] -1 - (toluene-4-sulfonyl) -1 H-indol- 6- ilmethyl] -piperazin -1-yl} -ethanone 651
- 1339 1339
- £ XijCÉRL-. 5-0r p [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpirazol- 4-il] - [1-bencenosulfonil-5-(4-metilpiperazin- 1 -ilmetil)-1 H-indol- 2-il] -metanona 609 £ XijCÉRL-. 5-0r p [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpyrazol- 4-yl] - [1-benzenesulfonyl-5- (4-methylpiperazin-1-methylmethyl) -1 H-indole-2-yl] -methanone 609
- 1340 1340
- «2 ajCcKr [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpirazol- 4-il] - (1-bencenosulfonil-5-pirrolidin-1-ilmetil-1 H-indol-2-il)- metanona 580 «2 ajCcKr [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 Hpirazol-4-yl] - (1-benzenesulfonyl-5-pyrrolidin-1-ylmethyl-1 H-indole-2 -il) - methanone 580
- 1341 1341
- e ^ty-r [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpirazol- 4-il] - [6-pirrolidin-1-ilmetil-1-(tolueno-4- sulfonil)-1 H-indol-2-il] - metanona 594 e ^ ty-r [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpyrazol-4-yl] - [6-pyrrolidin-1-ylmethyl-1- (toluene-4-sulfonyl ) -1 H-indole-2-yl] - methanone 594
- 1342 1342
- JXCÜ-C^ [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpirazol- 4-il] - [6-(4-hidroxi-piperidin-1-ilmetil) -1-(tolueno-4-sulfonil)-1H- indol-2-il] -metanona 624 JXCÜ-C ^ [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 Hpirazol-4-yl] - [6- (4-hydroxy-piperidin-1-ylmethyl) -1- ( toluene-4-sulfonyl) -1H- indole-2-yl] -methanone 624
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1343 1343
- í. [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpirazol- 4-il] -[6-piperadin-1-ilmetil)-1-(tolueno -4- sulfonil)-1 H-indol-2- il] -metanona 609 í. [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1-pyrazol-4-yl] - [6-piperadin-1-ylmethyl) -1- (toluene -4-sulfonyl) -1 H -indole-2- il] -methanone 609
- 1344 1344
- OjOK.-. ! [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpirazol- 4-il] -[5-((R)-3-metil-morfolin-4-ilmetil)- 1-(tolueno-4-sulfonil) - 1 H-indol-2-il]-metanona 624 OjOK.-. ! [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1-pyrazol-4-yl] - [5 - ((R) -3-methyl-morpholin-4-ylmethyl) -1- ( toluene-4-sulfonyl) - 1 H-indol-2-yl] -methanone 624
- 1345 1345
- £ [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpirazol- 4-il] -[6-((R)-3-fluoro-pi rrolidin-1-ilmetil)- 1-(tolueno-4-sulfonil) -1 H-indol-2-il]-metanona 612 £ [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1-pyrazol-4-yl] - [6 - ((R) -3-fluoro-pi rrolidin-1-ylmethyl) - 1 - (toluene-4-sulfonyl) -1 H-indol-2-yl] -methanone 612
- 1346 1346
- ^X'ic9- [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpirazol- 4-il] -[5-(2,5-dimetil-pirrolidin-1 -ilmetil)- 1-(tolueno-4-sulfonil)- 1 H-indol-2-il]-metanona 622 ^ X'ic9- [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 Hpirazol-4-yl] - [5- (2,5-dimethyl-pyrrolidin-1-ylmethyl) - 1- (toluene-4-sulfonyl) - 1 H-indol-2-yl] -methanone 622
- 1347 1347
- jDJXK^ , 1 [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpirazol- 4-il] -[5-(3-fluoro-piperidin-1 -ilmetil) -1-(tolueno-4-sulfonil)-1H- indol-2-il] -metanona 626 jDJXK ^, 1 [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hyrazol- 4-yl] - [5- (3-fluoro-piperidin-1-methylmethyl) -1- ( toluene-4-sulfonyl) -1H- indole-2-yl] -methanone 626
- 1348 1348
- ■t JXOHr ^xxr [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpirazol- 4-il] -[5-(3,3-difluoro-piperidin-1-ilmetil) -1-(tolueno-4-sulfonil)- 1 H-indol-2-il] -metanona 644 ■ t JXOHr ^ xxr [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 Hpirazol-4-yl] - [5- (3,3-difluoro-piperidin-1-ylmethyl) - 1- (toluene-4-sulfonyl) - 1 H-indol-2-yl] -methanone 644
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1349 1349
- [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpi razol- 4-il] -[5-(4-fluoro-piperidi n-1-ilmetil) -1-(tolueno-4- sulfonil)-1 H-indol-2-il] -metanona 626 [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpi razol-4-yl] - [5- (4-fluoro-piperidi n-1-ylmethyl) -1- (toluene- 4- sulfonyl) -1 H-indole-2-yl] -methanone 626
- 1350 1350
- ó - Ü'-A> "Oj03-L-. [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpi razol- 4-il] -[5-(4,4-difluoro-piperidin-1 -ilmetil) -1-(tolueno-4- sulfonil)-1 H-indol-2-il] -metanona 644 or - Ü'-A> "Oj03-L-. [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpi razol-4-yl] - [5- (4,4- difluoro-piperidin-1-methylmethyl) -1- (toluene-4-sulfonyl) -1 H-indole-2-yl] -methanone 644
- 1351 1351
- ■í, <FO±Lr ■ -'Gr [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpi razol- 4-il] -[6-(3-fluoro-piperidi n-1-ilmetil) -1-(tolueno-4- sulfonil)-1 H-indol-2-il] -metanona 626 ■ í, <FO ± Lr ■ -'Gr [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpi razol-4-yl] - [6- (3-fluoro-piperidi n -1-ilmethyl) -1- (toluene-4-sulfonyl) -1 H-indole-2-yl] -methanone 626
- 1352 1352
- -* v"0>- [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpi razol- 4-il] -[6-{[bis-(2-metoxi-etil)-amino] -metil- 1-(tolueno- 4-sulfonil)-1H-indol-2-il]-metanona 656 - * v "0> - [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpi razol-4-yl] - [6 - {[bis- (2-methoxy-ethyl) -amino] -methyl- 1- (toluene-4-sulfonyl) -1H-indole-2-yl] -methanone 656
- 1353 1353
- ^-co- [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpi razol- 4-il] -[5-(3,3 -difluoro-pirrolidin-1-ilmetil) -1-(tolueno-4- sulfonil) -1 H-indol-2-il]-metanona 630 ^ -co- [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpi razol-4-yl] - [5- (3,3-difluoro-pyrrolidin-1-ylmethyl) - 1- (toluene-4-sulfonyl) -1 H-indol-2-yl] -methanone 630
- 1354 1354
- [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpi razol- 4-il] -{6-[(metil-prop-2-inil-amino) -metil]- 1-(tolueno-4- sulfonil)-1H-indol-2-il}-metanona 592 [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpi razol-4-yl] - {6 - [(methyl-prop-2-inyl-amino) -methyl] - 1- (toluene-4-sulfonyl) -1H-indole-2-yl} -methanone 592
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1355 1355
- [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4-il] -[6-(3,3 -difluoro-pirrolidi n-1-ilmetil)- 1-(tolueno-4- sulfonil) -1 H-indol-2-il]-metanona 630 [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4-yl] - [6- (3,3-difluoro-pyrrolidi n-1-ylmethyl) - 1- (toluene-4-sulfonyl) -1 H-indol-2-yl] -methanone 630
- 1356 1356
- broZL*, [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4-il] -[6-(2,5-dimetil-pirrolidin-1-ilmetil) -1-(tolueno-4- sulfonil) -1 H-indol-2-il]-metanona 622 broZL *, [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4-yl] - [6- (2,5-dimethyl-pyrrolidin-1-ylmethyl) - 1- (toluene-4-sulfonyl) -1 H-indol-2-yl] -methanone 622
- 1357 1357
- r ^xxr [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4-il] -[6-(3,3-difluoro-piperidin-1-ilmetil) -1-(tolueno-4- sulfonil) -1 H-indol-2-il]-metanona 644 r ^ xxr [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4-yl] - [6- (3,3-difluoro-piperidin-1-ylmethyl) - 1- (toluene-4-sulfonyl) -1 H-indol-2-yl] -methanone 644
- 1358 1358
- 1 [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4-il] -[6-((S)-3-metil-morfolin-4-ilmetil)- 1-(tolueno-4- sulfonil) -1 H-indol-2-il]-metanona 624 1 [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4-yl] - [6 - ((S) -3-methyl-morpholin-4-ylmethyl) - 1- (toluene-4-sulfonyl) -1 H-indol-2-yl] -methanone 624
[Ejemplos 196 y 197][Examples 196 and 197]
Los compuestos de los Ejemplos 196 y 197 enumerados en la Tabla 15, se sintetizaron mediante el mismo método 5 como en la Etapa 8.The compounds of Examples 196 and 197 listed in Table 15, were synthesized by the same method 5 as in Step 8.
- Ejemplo Example
- Estructura Nombre del compuesto m/z RMN Structure Name of compound m / z NMR
- 196 196
- [5-amlno-1-(2-metil- 1H-benc¡m¡dazol -5-il)- IHpirazol- 4-¡l]-[6-(4,4- difluoro -piperldin-1- ilmetil)-1 H-indol-2-il] - metanona 490 1H-RMN (DMSO-D6) 8: 12.46 (1 .OH, s), 11.65 (1 .OH, s), 8.30 (1 OH, s), 7.64 (3.OH, m), 7.42 (2.0H, t, J =2.4 Hz), 7.30 (1 .OH, dd, J = 8.3, 2.0 Hz), 7.07 (1.0H, dd, J = 8.3, 1.0 Hz), 7.00 (2.0H, m), 3.64 (3.OH, s), 2.55-2.48 (4.2H, m), 2.54 (2.5H, s), 2.01-1.91 (4.2H, m). [5-amlno-1- (2-methyl- 1H-benzyldazol-5-yl) - I-pyrazol-4-yl] - [6- (4,4- difluoro -piperldin-1- ylmethyl) - 1 H-indole-2-yl] - methanone 490 1 H-NMR (DMSO-D6) 8: 12.46 (1 .OH, s), 11.65 (1 .OH, s), 8.30 (1 OH, s), 7.64 ( 3.OH, m), 7.42 (2.0H, t, J = 2.4 Hz), 7.30 (1 .OH, dd, J = 8.3, 2.0 Hz), 7.07 (1.0H, dd, J = 8.3, 1.0 Hz) , 7.00 (2.0H, m), 3.64 (3.OH, s), 2.55-2.48 (4.2H, m), 2.54 (2.5H, s), 2.01-1.91 (4.2H, m).
- 197 197
- ■■O'OHcyr [5-am¡no-1-(2-metil- 1H-bencimidazol -5-il)- 1 Hpirazol- 4-¡l]-[6-(4- fluoro -piperidin-1- ilmetil)-1 H-indol- 2-il] - metanona 472 1H-RMN (DMSO-D6) 8: 12.46 (1 OH, s), 11.63 (1 OH, s), 8.30 (1 OH, s), 7.62 (3.OH, m), 7.41 (2.0H, d, J = 5.9 Hz), 7.30 (1 .OH, dd, J = 8.5, 2.2 Hz), 7.05 (1 .OH, dd, J = 8.3, 1.0 Hz), 7.00 (2H, m), 4.69 (1 .OH, m), 3.56 (2.0H, s), 2.60.2.50 (2.OH, m), 2.54 (3H, s), 2.37- 2.26 (2.OH, m), 1.94-1.78 (2.0H, m), 1.78-1.65 (2.OH, m). ■■ O'OHcyr [5-amine-1- (2-methyl- 1H-benzimidazol -5-yl) - 1 Hpyrazol- 4-yl] - [6- (4- fluoro -piperidin-1- ylmethyl ) -1 H-indole-2-yl] - methanone 472 1 H-NMR (DMSO-D6) 8: 12.46 (1 OH, s), 11.63 (1 OH, s), 8.30 (1 OH, s), 7.62 ( 3.OH, m), 7.41 (2.0H, d, J = 5.9 Hz), 7.30 (1 .OH, dd, J = 8.5, 2.2 Hz), 7.05 (1 .OH, dd, J = 8.3, 1.0 Hz ), 7.00 (2H, m), 4.69 (1 .OH, m), 3.56 (2.0H, s), 2.60.2.50 (2.OH, m), 2.54 (3H, s), 2.37-2.26 (2. OH, m), 1.94-1.78 (2.0H, m), 1.78-1.65 (2.OH, m).
Etapa 9: Síntesis de 1-(4-{2-[5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-p¡razol-4-carbonil]-1-bencenosulfon¡l-1- ¡ndol-5-llmetil}-p¡peraz¡n-1-¡l)-etanona (1359)Stage 9: Synthesis of 1- (4- {2- [5-amino-1- (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-carbonyl] -1-benzenesulfon¡l-1- ndol-5-llmetil} -p¡peraz¡n-1-¡l) -ethanone (1359)
La [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-(5-piperaz¡n-1-¡lmet¡l 1-1H-indol-2-¡l)-metanona (103 mg) se disolvió en una solución acuosa saturada de bicarbonato de sodio (25 mi) que contiene dlclorometano (20 mi) y metanol (3 mi), y se enfrió a 0°C. A continuación, se le adicionó acetil cloruro (326 pl) en tres partes, y se agitó, durante 1.5 horas. La mezcla de reacción se extrajo con diclorometano. El extracto se secó sobre sulfato de sodio 10 anhidro. El desecante se eliminó por filtración, y el filtrado se concentró bajo presión reducida. El residuo resultante se purificó por cromatografía de columna de síllca gel (metanol/diclorometano = 0/100 a 10/100) para dar la 1-(4-{2- [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-carbon¡l]-1-bencenosulfonil-1-¡ndol-5-ilmetil}- pi pe razi n-1 -i I )-The [5-am-1-1 (2-methyl-1H-benzyldazol-5-l) -1H-prazol-4-l] - (5-piperazine) 1-lmet¡l 1-1H-indole-2-l) -methanone (103 mg) was dissolved in a saturated aqueous solution of sodium bicarbonate (25 ml) containing dichloromethane (20 ml) and methanol (3 ml ), and cooled to 0 ° C. Then, acetyl chloride (326 pl) was added in three parts, and stirred, for 1.5 hours. The reaction mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol / dichloromethane = 0/100 to 10/100) to give 1- (4- {2- [5-amine-1- (2-met! l-1H-benzyldazol-5-¡) -1H-p¡razol-4-carbon¡l] -1-benzenesulfonyl-1-¡-ol-5-ylmethyl} - pi pe razi n-1 - i I) -
etanona (32 mg).ethanone (32 mg).
1H-RMN (CDCIs) 8: 8.18-8.14 (2.0H, m), 8.05 (1 .OH, d, J = 8.8 Hz), 7.78 (1.1H, s), 7.60-7.56 (1.0H, m), 7.50 (3.0H, 15 m), 7.40 (1 .OH, dd, J = 8.8, 1.5 Hz), 7.35 (1 .OH, m), 6.98 (1.0H, s), 6.03 (2.0H, m), 3.62 (2.0H, t, J = 5.0 Hz), 3.581 H-NMR (CDCIs) 8: 8.18-8.14 (2.0H, m), 8.05 (1 .OH, d, J = 8.8 Hz), 7.78 (1.1H, s), 7.60-7.56 (1.0H, m), 7.50 (3.0H, 15 m), 7.40 (1 .OH, dd, J = 8.8, 1.5 Hz), 7.35 (1 .OH, m), 6.98 (1.0H, s), 6.03 (2.0H, m), 3.62 (2.0H, t, J = 5.0 Hz), 3.58
(2.OH, s), 3.45 (2.OH, t, J = 5.0 Hz), 2.64 (3.0H, s), 2.42 (4.0H, m), 2.07 (3.0H, s)(2.OH, s), 3.45 (2.OH, t, J = 5.0 Hz), 2.64 (3.0H, s), 2.42 (4.0H, m), 2.07 (3.0H, s)
ESI (LC-MS modo positivo) m/z 637 [(M+H)+]ESI (LC-MS positive mode) m / z 637 [(M + H) +]
Etapa 10: Síntesis de 5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[1-bencenosulfonil-5-(4-Stage 10: Synthesis of 5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [1-benzenesulfonyl-5- (4-
metanosulfonilpiperazin-1-ilmetil)-1H-indol-2-il]-metanona (1360)methanesulfonylpiperazin-1-ylmethyl) -1H-indol-2-yl] -methanone (1360)
La [5-amino-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-il]-(5-piperazin-1-¡lmetil 1-1H-indol-2-il)-metanona (94 mg) se disolvió en tetrahidrofurano (THF) (5 mi) y una solución acuosa saturada de bicarbonato de sodio (5 mi), y se enfrió a 0°C. A continuación se le adicionó cloruro de metanosulfonilo (94 pl) y se agitó a 0°C, durante 1.5 horas. A 5 continuación, se le adicionó agua de amoníaco (5 mi), y se agitó a 0°C, durante dos horas. La mezcla de reacción se extrajo con acetato de etilo, y el extracto se lavó con una solución saturada de cloruro de sodio y se secó sobre sulfato de sodio anhidro. El desecante se eliminó por filtración. El filtrado se concentró bajo presión reducida. El residuo resultante se purificó por cromatografía de columna de sílica gel (metanol/diclorometano =0/100 a 15/100) para dar la 5-amino-1-(2-met¡l-1H-bencimidazol-5-¡l)-1H-pirazol-4-il]-[1-bencenosulfonil-5-(4-metano sulfonilpiperazin- 10 1-ilmetll)- 1H-¡ndol-2-il]-metanona (39 mg).[5-Amino-1- (2-methyl-1H-benzyldazol-5-yl) -1 H -pyrazol-4-yl] - (5-piperazin-1-methyl-1) -1H-indole-2-yl) -methanone (94 mg) was dissolved in tetrahydrofuran (THF) (5 ml) and a saturated aqueous solution of sodium bicarbonate (5 ml), and cooled to 0 ° C. Then methanesulfonyl chloride (94 pl) was added and stirred at 0 ° C for 1.5 hours. Then, ammonia water (5 ml) was added and stirred at 0 ° C for two hours. The reaction mixture was extracted with ethyl acetate, and the extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol / dichloromethane = 0/100 to 15/100) to give 5-amino-1- (2-methyl-1H-benzimidazole-5-l) -1H-pyrazol-4-yl] - [1-benzenesulfonyl-5- (4-methane sulfonylpiperazin-10 1-ylmetll) - 1H-¡ndol-2-yl] -methanone (39 mg).
1H-RMN (CD3OD) 8: 8.09 (2.0H, m), 7.98 (2.0H, m), 7.84 (1.0H, m), 7.75 (1.0H, m), 7.65-7.57 (3.0H ,m), 7.53-7.40 (3.OH, m), 7.12 (1 .OH, d, J = 3.9 Hz), 3.64 (2.0H, m), 3.25-3.15 (4.0H, m), 2.86 (3.0H, s), 2.82 (3.0H, s), 2.54 (4.0H,1H-NMR (CD3OD) 8: 8.09 (2.0H, m), 7.98 (2.0H, m), 7.84 (1.0H, m), 7.75 (1.0H, m), 7.65-7.57 (3.0H, m), 7.53-7.40 (3.OH, m), 7.12 (1 .OH, d, J = 3.9 Hz), 3.64 (2.0H, m), 3.25-3.15 (4.0H, m), 2.86 (3.0H, s) , 2.82 (3.0H, s), 2.54 (4.0H,
m)m)
ESI (LC-MS modo positivo) m/z 673 [(M+H)+jESI (LC-MS positive mode) m / z 673 [(M + H) + j
15 Etapa 11: Síntesis del éster etílico del ácido 5-isopropoxi-1-(tolueno-4-sulfonil)- 1H-indol-2-carboxílico (1361)Step 11: Synthesis of the 5-isopropoxy-1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid ethyl ester (1361)
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Se adicionó düsopropll azodlcarboxllato (0.15 mi, 0.75 mmol) a una solución en tetrahidrofurano (THF) anhidro (2.5 mi) de éster etílico del ácido 5-h¡drox¡-1-(tolueno-4-sulfonil)-1H-indol-2-carboxílico (175 mg, 0.48 mmol), trifenilfosfina (197 mg, 0.75 mmol), y 2-propanol (0.2 mi, 4.0 mmol), y se agitó a temperatura ambiente, durante una hora. La 20 mezcla de reacción se concentró bajo presión reducida. El residuo resultante se purificó por cromatografía de columna de sílica gel para dar el éster etílico del ácido 5-isopropoxi-1-(tolueno-4-sulfonil)- 1H-indol-2-carboxílico como un material como goma Incoloro (166.7 mg, 87%).Düsopropll azodlcarboxllate (0.15 ml, 0.75 mmol) was added to a solution in anhydrous tetrahydrofuran (THF) (2.5 ml) of 5-hydroxyl-1- (toluene-4-sulfonyl) -1H-indole- ethyl ester 2-carboxylic (175 mg, 0.48 mmol), triphenylphosphine (197 mg, 0.75 mmol), and 2-propanol (0.2 mL, 4.0 mmol), and stirred at room temperature, for one hour. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the 5-isopropoxy-1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid ethyl ester as a material such as Colorless gum (166.7 mg, 87%)
1H-RMN (DMSO-De) 8: 7.86 (1H, d, J = 9.1 Hz), 7.79 (2H, d, J = 8.5 Hz), 7.39 (2H, d, J = 8.5 Hz), 7.25 (1H, s), 7.15 (1H, d, J = 2.4 Hz), 7.04 (1H, dd, J = 9.1, 2.4 Hz), 4.62-4.53 (1H, m), 4.34 (2H, q, J = 7.1 Hz), 2.34 (3H, s), 1.31 (3H, 25 t, J =7.1 Hz), 1.25 (6H, d, J =6.1 Hz)1H-NMR (DMSO-De) 8: 7.86 (1H, d, J = 9.1 Hz), 7.79 (2H, d, J = 8.5 Hz), 7.39 (2H, d, J = 8.5 Hz), 7.25 (1H, s), 7.15 (1H, d, J = 2.4 Hz), 7.04 (1H, dd, J = 9.1, 2.4 Hz), 4.62-4.53 (1H, m), 4.34 (2H, q, J = 7.1 Hz), 2.34 (3H, s), 1.31 (3H, 25 t, J = 7.1 Hz), 1.25 (6H, d, J = 6.1 Hz)
ESI (LC-MS modo positivo) m/z 402 [(M+H)+jESI (LC-MS positive mode) m / z 402 [(M + H) + j
Los compuestos de los números 1362 a 1367 enumerados en la Tabla 16, se sintetizaron mediante el mismo método como en la Etapa 11.The compounds of Nos. 1362 to 1367 listed in Table 16, were synthesized by the same method as in Step 11.
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1362 1362
- $ cr~ éster metílico del ácido 6-(2-morfolin-4-il-etoxi)-1- (tolueno-4-sulfonil)-1 H-indol -2-carboxílico 459 Cr ~ 6- (2-morpholin-4-yl-ethoxy) -1- (toluene-4-sulfonyl) -1 H-indole -2-carboxylic acid methyl ester 459
- 1363 1363
- ¿ CfX&L éster metílico del ácido 6-(tetrahidro-piran-4-iloxi) -1- (tolueno-4-sulfonil)-1 H-indol- 2-carboxílico 430 CfX & L 6- (tetrahydro-pyran-4-yloxy) -1- (toluene-4-sulfonyl) -1 H-indole-2-carboxylic acid methyl ester 430
- 1364 1364
- oP XT'XXH- éster metílico del ácido 1-bencenosulfonil-6-[2-(4-metil- piperadin-1-il)-etoxi]-1H-indol-2-carboxílico 458 oP XT'XXH- 1-benzenesulfonyl-6- [2- (4-methyl-piperadin-1-yl) -ethoxy] -1H-indole-2-carboxylic acid methyl ester 458
- 1365 1365
- i / éster metílico del ácido 4-isopropoxi-1H-indol-2- carboxílico 234 i / 4-Isopropoxy-1H-indole-2-carboxylic acid methyl ester 234
- 1366 1366
- $ S,¡JtO éster etílico del ácido 5-(2-metoxi-etoxi)-1-(tolueno-4- sulfonil)-1 H-indol -2- carboxílico 416 S, JtO 5- (2-methoxy-ethoxy) -1- (toluene-4-sulfonyl) -1 H-indole -2-carboxylic acid ethyl ester 416
- 1367 1367
- Si- ¿ [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol -4- il]-[6-(3-metil-oxetan-3-ilmetoxi)-1-(tolueno-4- sulfonil) - 1 H-indol-2-il]-metanona 611 Si- ¿[5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol -4-yl] - [6- (3-methyl-oxetan-3-ylmethoxy) -1- (toluene-4-sulfonyl) - 1 H-indol-2-yl] -methanone 611
Etapa 12: Síntesis del éster etílico del ácido 5-ciclopropilmetoxi-1-(tolueno-4-sulfonil)- 1H-indol-2-carboxílico (1368)Step 12: Synthesis of 5-cyclopropylmethoxy-1- (toluene-4-sulfonyl) - 1H-indole-2-carboxylic acid ethyl ester (1368)
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Se adicionó bromuro de ciclopropilmetilo (0.072 mi, 0.75 mmol) a una suspensión (5.0 mi) del áster etílico del ácidoCyclopropylmethyl bromide (0.072 ml, 0.75 mmol) was added to a suspension (5.0 ml) of the ethyl acid ester
5-hidroxi-1-(tolueno- 4-sulfonil)- 1H-indol-2-carboxílico (173 mg, 0.48 mmol) y carbonato de potasio (276 mg, 1.0 mmol) en acetonitrilo, y se agitó a 80°C, durante cinco horas. Después de enfriar a temperatura ambiente, la mezcla 5 de reacción se combinó con acetato de etilo y agua y se extrajo con acetato de etilo. El extracto se lavó con agua y una solución acuosa saturada de cloruro de sodio, y se secó sobre sulfato de sodio anhidro. El desecante se eliminó por filtración. El filtrado se concentró bajo presión reducida. El residuo resultante se purificó por cromatografía de columna de sílica gel para dar el áster etílico del ácido 5-ciclopropilmetoxi-1-(tolueno-4-sulfonil)- 1H-indol-2- carboxílico como un material como goma incolora (112.5 mg, 56%).5-hydroxy-1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid (173 mg, 0.48 mmol) and potassium carbonate (276 mg, 1.0 mmol) in acetonitrile, and stirred at 80 ° C, for five hours After cooling to room temperature, the reaction mixture was combined with ethyl acetate and water and extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give the 5-cyclopropylmethoxy-1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid ethyl ester as a colorless gum material (112.5 mg, 56%)
10 1H-RMN (DMSO-De) 8: 7.87 (1H, d, J = 9.2 Hz), 7.76 (2H, d, J = 8.2 Hz), 7.38 (2H, d, J = 8.2 Hz), 7.25 (1H, s), 7.11 (1H, d, J =2.6 Hz), 7.07 (1H, dd, J = 9.2, 2.6 Hz), 4.33 (2H, q, J = 8.1 Hz), 3.80 (2H, d, J = 6.6 Hz), 2.33 (3H, s), 1.32 (3H, t, J = 8.1 Hz), 1.25-1.19 (1H, m), 0.58-0.52 (2H, m), 0.33-0.28 (2H, m)10 1H-NMR (DMSO-De) 8: 7.87 (1H, d, J = 9.2 Hz), 7.76 (2H, d, J = 8.2 Hz), 7.38 (2H, d, J = 8.2 Hz), 7.25 (1H , s), 7.11 (1H, d, J = 2.6 Hz), 7.07 (1H, dd, J = 9.2, 2.6 Hz), 4.33 (2H, q, J = 8.1 Hz), 3.80 (2H, d, J = 6.6 Hz), 2.33 (3H, s), 1.32 (3H, t, J = 8.1 Hz), 1.25-1.19 (1H, m), 0.58-0.52 (2H, m), 0.33-0.28 (2H, m)
ESI (LC-MS modo positivo) m/z 414 [(M+H)+jESI (LC-MS positive mode) m / z 414 [(M + H) + j
[Ejemplo 198: Síntesis de [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(oxetan-3-iloxi)-1H-indol- 2-il]- 15 metanona][Example 198: Synthesis of [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [6- (oxetan-3-yloxy) -1H-indole - 2-il] - 15 methanone]
Se disolvieron [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(6-hidroxi-1H-indol-2 -il)-metanona (21 mg, 0.056 mmol), áster del ácido oxetan-3-il tolueno-4- sulfónico (19 mg, 0.084 mmol), y carbonato de potasio (13 mg, 0.095 mmol) en N,N-dimetilformamida (DMF) anhidra, y se calentó a 80°C con agitación bajo una atmósfera de 20 nitrógeno, durante seis días. Después de enfriar a temperatura ambiente, la mezcla de reacción se combinó con agua, y se extrajo con una solución de acetato de etilo/metanol (10/1). La capa orgánica se aisló, se lavó con agua, y se secó sobre sulfato de magnesio anhidro. El desecante se eliminó por filtración. El filtrado se concentró bajo presión reducida. El residuo resultante se purificó por cromatografía de columna de sílica gel (diclorometano/metanol =100/3) para dar la [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-(oxetan-3-iloxi)-1H-indol-2-il]- 25 metanona como un sólido de color amarillo (6.9 mg, 29%).[5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (6-hydroxy-1H-indole-2-yl) -methanone (21 mg) , 0.056 mmol), oxetan-3-yl toluene-4-sulfonic acid ester (19 mg, 0.084 mmol), and potassium carbonate (13 mg, 0.095 mmol) in anhydrous N, N-dimethylformamide (DMF), and heated at 80 ° C with stirring under an atmosphere of 20 nitrogen, for six days. After cooling to room temperature, the reaction mixture was combined with water, and extracted with a solution of ethyl acetate / methanol (10/1). The organic layer was isolated, washed with water, and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol = 100/3) to give [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4 -il] - [6- (oxetan-3-yloxy) -1H-indole-2-yl] - 25 methanone as a yellow solid (6.9 mg, 29%).
1H-RMN (DMSO-De) 8: 12.48 (1.0H, brs), 11.48 (1.0H, brs), 8.28 (1.0H, s), 7.62-7.60 (3.0H, m), 7.41 (1.0H, brs), 7.28 (1 .OH, dd, J = 8.3, 2.0 Hz), 6.96 (1.0H, brs), 6.94 (1.0H, brs), 6.71 (1.0H, dd, J = 8.5, 2.2 Hz), 6.67 (1.0H, brs), 5.34- 5.29 (1 .OH, m), 4.94 (2.0H, dd, J = 6.8, 6.8 Hz), 4.60 (2.0H, dd, J = 6.8, 5.1 Hz), 2.53 (3.0H, s)1H-NMR (DMSO-De) 8: 12.48 (1.0H, brs), 11.48 (1.0H, brs), 8.28 (1.0H, s), 7.62-7.60 (3.0H, m), 7.41 (1.0H, brs ), 7.28 (1 .OH, dd, J = 8.3, 2.0 Hz), 6.96 (1.0H, brs), 6.94 (1.0H, brs), 6.71 (1.0H, dd, J = 8.5, 2.2 Hz), 6.67 (1.0H, brs), 5.34-5.29 (1 .OH, m), 4.94 (2.0H, dd, J = 6.8, 6.8 Hz), 4.60 (2.0H, dd, J = 6.8, 5.1 Hz), 2.53 ( 3.0H, s)
ESI (LC-MS modo positivo) m/z 429 [(M+H)+jESI (LC-MS positive mode) m / z 429 [(M + H) + j
30 [Ejemplo 199: Síntesis de [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(6-hidroxi-1H-indol-2-il)- metanona][Example 199: Synthesis of [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (6-hydroxy-1H-indole-2-yl) - methanone]
55
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3535
ho^^nho ^^ n
Se disolvieron 2-[5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-carbonil]-1-(tolueno-4-sulfonil)-1H-indol-6- carbaldehído (650 mg, 1.0 mmol), 1,1’-bis(difenilfosfino)ferroceno paladio(ll) dicloruro (42 mg, 0.051 mmol), bis(pinacolato) diboro (312 mg, 1.23 mmol), y acetato de potasio (323 mg, 3.3 mmol) en N,N-dimetilformamida (DMF) anhidra (4.1 mi). Después de la desaireación, la mezcla se calentó a 100°C con agitación bajo una atmósfera de nitrógeno, durante ocho horas. La mezcla de reacción se enfrió a temperatura ambiente, y a continuación, se le adicionó agua. El sólido precipitado se recolectó por filtración, se lavó con agua, y a continuación se secó para dar un sólido de color marrón (538 mg). El producto en bruto obtenido se utilizó en reacciones posteriores sin purificación.2- [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-carbonyl] -1- (toluene-4-sulfonyl) -1 H -indole-6- carbaldehyde (650 mg, 1.0 mmol), 1,1'-bis (diphenylphosphino) ferrocene palladium (ll) dichloride (42 mg, 0.051 mmol), bis (pinacolato) diboro (312 mg, 1.23 mmol), and potassium acetate ( 323 mg, 3.3 mmol) in anhydrous N, N-dimethylformamide (DMF) (4.1 ml). After deaeration, the mixture was heated at 100 ° C with stirring under a nitrogen atmosphere, for eight hours. The reaction mixture was cooled to room temperature, and then water was added. The precipitated solid was collected by filtration, washed with water, and then dried to give a brown solid (538 mg). The crude product obtained was used in subsequent reactions without purification.
El producto en bruto obtenido sólido de color marrón de 4-metil-morfolina N-óxido (256 mg, 2.2 mmol) se disolvió en tetrahidrofurano (THF) (7.0 mi), y se calentó a 70°C con agitación bajo una atmósfera de nitrógeno, durante tres horas y media. Después la mezcla de reacción se enfrió a temperatura ambiente, se le adicionaron agua y acetato de etilo. La mezcla se filtró a través de Celite®, y el filtrado se disolvió en capas orgánica y acuosa. La capa orgánica se concentró bajo presión reducida, y el residuo resultante se purificó por cromatografía de columna de sílica gel (sílica amino; diclorometano /metanol = 100/5 a 100/10) para dar la [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H- pirazol- 4-il]-(6-hidroxi-1 H-indol-2-il)-metanona como un material amorfo de color amarillo (123 mg, con un rendimiento de dos etapas de 23%).The crude product obtained brown solid of 4-methyl-morpholine N-oxide (256 mg, 2.2 mmol) was dissolved in tetrahydrofuran (THF) (7.0 ml), and heated at 70 ° C with stirring under an atmosphere of nitrogen, for three and a half hours. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added. The mixture was filtered through Celite®, and the filtrate was dissolved in organic and aqueous layers. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (amino silica; dichloromethane / methanol = 100/5 to 100/10) to give [5-amino-1- (2 -methyl-1 H -benzimidazol-5-yl) -1 H- pyrazol-4-yl] - (6-hydroxy-1 H-indol-2-yl) -methanone as a yellow amorphous material (123 mg, with a 23% two stage yield).
1H-RMN (DMSO-De) 8: 12.51 (1 .OH, brs), 11.30 (1 .OH, brs), 9.40 (1 .OH, brs), 8.26 (1.0H, s), 7.61-7.59 (2.0H, m), 7.47 (1 .OH, d, J = 8.8 Hz), 7.34 (1 .OH, s), 7.28 (1 .OH, d, J = 8.8 Hz), 6.91 (2.0H, brs), 6.82 (1.0H, s), 6.62(1.OH, d, J = 8.8 Hz), 2.53 (3.OH, s)1 H-NMR (DMSO-De) 8: 12.51 (1 .OH, brs), 11.30 (1 .OH, brs), 9.40 (1 .OH, brs), 8.26 (1.0H, s), 7.61-7.59 (2.0 H, m), 7.47 (1 .OH, d, J = 8.8 Hz), 7.34 (1 .OH, s), 7.28 (1 .OH, d, J = 8.8 Hz), 6.91 (2.0H, brs), 6.82 (1.0H, s), 6.62 (1.OH, d, J = 8.8 Hz), 2.53 (3.OH, s)
ESI (LC-MS modo positivo) m/z 373 [(M+H)+jESI (LC-MS positive mode) m / z 373 [(M + H) + j
Etapa 13: Síntesis de la [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-yodo-1-(tolueno-4-sulfonil)- IHindol- 2-¡l]-metanona (1369)Step 13: Synthesis of [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [6-iodo-1- (toluene-4-sulfonyl) - IHindol- 2-¡] -methanone (1369)
o=s=oo = s = o
Una mezcla que consiste en [5-amino-1-(2-metil-3H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-bromo-1-(tolueno-4- sulfonil) -1H-indol-2-il]-metanona (1 g), yoduro de cobre (I) (161 mg), yoduro de sodio (508 mg), trans-N,N’- dimetilciclohexano- 1,2-diamina (267 pl), y dioxano anhidro (5 mi) se agitó en un recipiente a prueba de presión de 105 a 112°C, bajo una atmósfera de nitrógeno, durante 20 horas. La mezcla de reacción se vertió en una solución acuosa de amoníaco 2 M, y la mezcla se extrajo con acetato de etilo. La capa orgánica se lavó con una solución acuosa saturada de cloruro de sodio, y se secó sobre sulfato de sodio anhidro. El desecante se eliminó por filtración. El filtrado se concentró bajo presión reducida. El residuo resultante se purificó por cromatografía de columna de sílica gel (metanol/ diclorometano = 0/100 a 20/100) para dar la [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol- 4-¡l]-[6-yodo-1-(tolueno-4-sulfonil)-1 H-indol-2-il]-metanona (0.67 g, 62%). 1A mixture consisting of [5-amino-1- (2-methyl-3H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [6-bromo-1- (toluene-4-sulfonyl) - 1H-indole-2-yl] -methanone (1 g), copper (I) iodide (161 mg), sodium iodide (508 mg), trans-N, N'-dimethylcyclohexane-1,2-diamine (267 pl), and anhydrous dioxane (5 ml) was stirred in a pressure-proof vessel of 105 to 112 ° C, under a nitrogen atmosphere, for 20 hours. The reaction mixture was poured into a 2M aqueous solution of ammonia, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol / dichloromethane = 0/100 to 20/100) to give [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H -pyrazol- 4-¡1] - [6-iodo-1- (toluene-4-sulfonyl) -1 H-indol-2-yl] -methanone (0.67 g, 62%). one
1H-RMN (DMSO-Ds) 8: 12.44 (1 OH, s), 8.30 (1.0H, d, J = 0.6Hz), 7.98 (2.0H, d, J = 8.5 Hz), 7.75 (1.0H, s), 7.66 (1 .OH, dd, J = 8.2, 1.4 Hz), 7.51 (1.0H, d, J = 8.0 Hz), 7.46 (2.0H, d, J = 8.5 Hz), 7.28 (1.0H, d, J = 7.6 Hz), 7.23 (1 .OH, d, J = 0.4 Hz), 7.10-6.92 (2.0H, m), 2.53 (3.0H, s), 2.37 (3.0H, s)1H-NMR (DMSO-Ds) 8: 12.44 (1 OH, s), 8.30 (1.0H, d, J = 0.6Hz), 7.98 (2.0H, d, J = 8.5 Hz), 7.75 (1.0H, s ), 7.66 (1 .OH, dd, J = 8.2, 1.4 Hz), 7.51 (1.0H, d, J = 8.0 Hz), 7.46 (2.0H, d, J = 8.5 Hz), 7.28 (1.0H, d , J = 7.6 Hz), 7.23 (1 .OH, d, J = 0.4 Hz), 7.10-6.92 (2.0H, m), 2.53 (3.0H, s), 2.37 (3.0H, s)
ESI (LC-MS modo positivo) m/z 637 [(M+H)+]ESI (LC-MS positive mode) m / z 637 [(M + H) +]
Los compuestos de los números 1370 y 1371 enumerados en la Tabla 17, se sintetizaron mediante el mismo método como en la Etapa 13.The compounds of Nos. 1370 and 1371 listed in Table 17, were synthesized by the same method as in Step 13.
Tabla 17Table 17
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1370 1370
- $ 0=4=0^ [5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol -4-¡l]-[5- yodo-1 -(tolueno-4-sulfonil)-1 H-indol-2-il] -metanona 637 $ 0 = 4 = 0 ^ [5-am-1-1- (2-methyl-1H-benzyldazol-5-l) -1 H-p.razole -4-l] - [ 5- iodine-1 - (toluene-4-sulfonyl) -1 H-indol-2-yl] -methanone 637
- 1371 1371
- éster etílico del ácido 1-bencenosulfonll-4-yodo-1H-lndol-2- carboxíllco 456 1-benzenesulfonll-4-iodo-1H-lndol-2-carboxylic acid ethyl ester 456
- z z
Etapa 14: Síntesis de 2-[5-amino-1-(2-met¡l-1H-bencim¡dazol-5-il)-1H-pirazol-4-carbon¡l]-1-(bencenosulfon¡l)-1H indol- 5-carbonitrilo (1372)Stage 14: Synthesis of 2- [5-amino-1- (2-methyl-1H-benzimdadazol-5-yl) -1H-pyrazol-4-carbonl] -1- (benzenesulfonyl) -1H indole-5-carbonitrile (1372)
Una mezcla de 2-[5-amino-1-(2-met¡l-1H-bencimidazol-5-¡l)-1H-pirazol-4-carbonil]-1-(bencenosulfonil)-5 -yodo- 1H- 10 indol (117 mg), cobre (I) cianuro (84 mg), y 1-met¡l-2-pirrol¡d¡nona se hizo reaccionar en un reactor de microondas (190°C, 20 minutos). La mezcla de reacción se vertió en una solución mixta de agua de amoníaco 2 M (40 mi), acetato de etilo (60 mi), y metanol (7 mi), y se sometió a sonicación durante cinco minutos. Después de la extracción con acetato de etilo, el extracto se lavó con agua y a continuación se secó sobre sulfato de sodio anhidro. El desecante se eliminó por filtración. El filtrado se concentró bajo presión reducida. El residuo resultante se purificó por 15 cromatografía de columna de sílica gel (metanol/diclorometano = 0/100 a 20/100) para dar 2-[5-amino-1-(2-metil-1H- bencimidazol-5-il)-1H-pirazol-4-carbonil]-1-(bencenosulfonil)-1 H-indol-5-carbonitrilo (87 mg, 89%).A mixture of 2- [5-amino-1- (2-methyl-1H-benzimidazol-5-α) -1H-pyrazol-4-carbonyl] -1- (benzenesulfonyl) -5-iodo-1H- 10 indole (117 mg), copper (I) cyanide (84 mg), and 1-methyl-2-pyrrolidone was reacted in a microwave reactor (190 ° C, 20 minutes). The reaction mixture was poured into a mixed solution of 2M ammonia water (40 ml), ethyl acetate (60 ml), and methanol (7 ml), and was sonicated for five minutes. After extraction with ethyl acetate, the extract was washed with water and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol / dichloromethane = 0/100 to 20/100) to give 2- [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1 H -pyrazol-4-carbonyl] -1- (benzenesulfonyl) -1 H-indole-5-carbonitrile (87 mg, 89%).
1H-RMN (DMSO-De) 8: 12.47 (1.0H, d, J = 8.4 Hz), 8.27-8.21 (4.0H, m), 7.86 (1.0H, dd, J = 8.8, 1.8 Hz), 7.80-7.76 (2.OH, m), 7.72-7.64 (3.0H, m), 7.60-7.55 (1.0H, m), 7.35-7.25 (2.0H, m), 7.12-7.02 (2.0H, m), 2.54 (3.0H, s) ESI (LC- MS modo positivo) m/z 522 [(M+H)+]1 H-NMR (DMSO-De) 8: 12.47 (1.0H, d, J = 8.4 Hz), 8.27-8.21 (4.0H, m), 7.86 (1.0H, dd, J = 8.8, 1.8 Hz), 7.80- 7.76 (2.OH, m), 7.72-7.64 (3.0H, m), 7.60-7.55 (1.0H, m), 7.35-7.25 (2.0H, m), 7.12-7.02 (2.0H, m), 2.54 (3.0H, s) ESI (LC-MS positive mode) m / z 522 [(M + H) +]
20 Los compuestos de los números 1373 y 1374 enumerados en la Tabla 18, se sintetizaron mediante el mismo método como en la Etapa 14.The compounds of Nos. 1373 and 1374 listed in Table 18, were synthesized by the same method as in Step 14.
Tabla 18Table 18
Etapa 15: Síntesis de 2-etil éster del ácido 1-(tolueno-4-sulfonil)-1H-indol-2,5-dicarboxílico (1375)Step 15: Synthesis of 2-ethyl ester of 1- (toluene-4-sulfonyl) -1H-indole-2,5-dicarboxylic acid (1375)
ATO
Una mezcla de éster etílico del ácido 5-bromo-1-(tolueno-4-sulfonll)- 1H-indol-2-carboxíllco (948.4 mg, 2.24 mmol), 5 Tris(d¡benc¡l¡denacetona) dlpaladlo (0) (0.112 mmol, 103 mg), 4,5-bls(difenilfosfino)-9,9-dlmet¡lxantano (Xantphos) (0.225 mmol, 130 mg), monohldrato del formlato de litio (5.6 mmol, 394 mg), cloruro de litio (286 mg, 6.75 mmol), y N.N-dlmetilformamlda (DMF) anhidra (5.9 mi) se evacuó, y rellenó con argón. A continuación, se adicionaron a la mezcla N,N-düsoprop¡let¡l amina (4.5 mmol, 0.78 mi) y anhídrido acético (4.5 mmol, 0.43 mi), y se realizaron de nuevo la desalreación y el reemplazo de argón. El recipiente de reacción se colocó en un dispositivo de reacción 10 precalentado a 80°C y la mezcla de reacción se agitó, durante 20 horas. Después de enfriar a temperatura ambiente, la mezcla de reacción se diluyó con acetato de etilo y una solución acuosa de ácido clorhídrico 1 M, y se filtró a través de Celite. El filtrado resultante se lavó con ácido clorhídrico 1 M, agua, y una solución acuosa saturada de cloruro de sodio, y a continuación se secó sobre sulfato de sodio anhidro. El desecante se eliminó por filtración. El filtrado se concentró bajo presión reducida, y el residuo resultante se purificó por cromatografía de columna de síllca 15 gel (hexano/acetato de etilo = 5/1 a 1/3, y finalmente acetato de etllo/metanol = 15/1) para dar el 2- etil éster del ácido 1-(tolueno-4-sulfonil)-1H-indol-2,5-dlcarboxíllco como un material amorfo de color amarillo (930 mg). 1A mixture of 5-bromo-1- (toluene-4-sulfonll) -1H-indole-2-carboxylic acid ethyl ester (948.4 mg, 2.24 mmol), 5 Tris (d-benzyl-ketone) dlpaladlo (0 ) (0.112 mmol, 103 mg), 4,5-bls (diphenylphosphino) -9,9-dlmetylxantane (Xantphos) (0.225 mmol, 130 mg), lithium formate monohydrate (5.6 mmol, 394 mg), chloride of lithium (286 mg, 6.75 mmol), and anhydrous NN-dlmethylformamlda (DMF) (5.9 ml) was evacuated, and filled with argon. Then, N, N-düsopropyl amine (4.5 mmol, 0.78 ml) and acetic anhydride (4.5 mmol, 0.43 ml) were added to the mixture, and the argon desalination and replacement were performed again. The reaction vessel was placed in a reaction device 10 preheated to 80 ° C and the reaction mixture was stirred for 20 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and a 1 M aqueous hydrochloric acid solution, and filtered through Celite. The resulting filtrate was washed with 1M hydrochloric acid, water, and a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1 to 1/3, and finally ethyl acetate / methanol = 15/1) to give the 2- ethyl ester of 1- (toluene-4-sulfonyl) -1H-indole-2,5-dlcarboxylic acid as a yellow amorphous material (930 mg). one
1H-RMN (DMSO-De) 8 : 8.32 (1H, d, J = 1.5 Hz), 8.13 (1H, d, J = 8.8 Hz), 8.05 (1H, dd, J = 8.8, 1.5 Hz), 7.93 (2H, d, J = 8.2 Hz), 7.50 (1H, s), 7.46 (2H, d, J = 8.2 Hz), 4.38 (2H, q, J = 7.1 Hz), 2.37 (3H, s), 1.34 (3H, t, J = 7.1 Hz)1H-NMR (DMSO-De) 8: 8.32 (1H, d, J = 1.5 Hz), 8.13 (1H, d, J = 8.8 Hz), 8.05 (1H, dd, J = 8.8, 1.5 Hz), 7.93 ( 2H, d, J = 8.2 Hz), 7.50 (1H, s), 7.46 (2H, d, J = 8.2 Hz), 4.38 (2H, q, J = 7.1 Hz), 2.37 (3H, s), 1.34 ( 3H, t, J = 7.1 Hz)
ESI (LC-MS modo positivo) m/z 388 [(M+H)+]ESI (LC-MS positive mode) m / z 388 [(M + H) +]
20 Síntesis del ácido 2-[5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-p¡razol-4-carbonil]-1-(tolueno-4-sulfonil) -1 H-indol- 6-carboxíllco (1376)Synthesis of 2- [5-amine-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-carbonyl] -1- (toluene-4-sulfonyl acid) ) -1 H-indole-6-carboxylic (1376)
HOHO
El ácido 2-[5-amino-1-(2-metil-1H-bencimidazol-5-¡l)-1H-p¡razol-4-carbonil]-1H-¡ndol-6- carboxílico se sintetizó por el mismo método como en la Etapa 15.2- [5-Amino-1- (2-methyl-1H-benzimidazol-5-α) -1 H -pyrazol-4-carbonyl] -1 H -indole-6- carboxylic acid was synthesized by it method as in Stage 15.
ESI (LC-MS modo positivo) m/z 555 [(M+H)+]ESI (LC-MS positive mode) m / z 555 [(M + H) +]
5 Etapa 16: Síntesis de 5-fe/í-butil éster2-etil áster del ácido 1-(tolueno-4-sulfonil)-1H-indol-2,5-dicarboxílico (1377)5 Step 16: Synthesis of 1- (toluene-4-sulfonyl) -1H-indole-2,5-dicarboxylic acid 5-fe / í-butyl ester 2-ethyl ester (1377)
El 2-etil éster del ácido 1-(Toluene-4-sulfonil)-1H-indol-2,5-dicarboxílico (690 mg, 1.85 mmol) se disolvió en N,N- dimetilformamida di-fe/f-butil acetal (3.0 mi), y se agitó a 80°C, durante dos horas y media. Adicionalmente se le adicionó N,N-dimetilformamida diferí- butil acetal (2.0 mi) y se agitó a 80°C, durante tres horas. Después de enfriar a 10 temperatura ambiente, la mezcla de reacción se diluyó con acetato de etilo (150 mi) y agua (75 mi). La capa orgánica se aisló, se lavó con agua y una solución acuosa saturada de cloruro de sodio, y a continuación se secó sobre sulfato de sodio anhidro. El desecante se eliminó por filtración. El filtrado se concentró bajo presión reducida. El residuo resultante se purificó por cromatografía de columna de síllca gel (hexano/acetato de etilo = 25/1 a 5/1) para dar el 5-fe/f-butil éster 2-etil éster del ácido 1-(tolueno-4-sulfonil)-1H-indol-2,5-dicarboxílico (551 mg, 69%).1- (Toluene-4-sulfonyl) -1H-indole-2,5-dicarboxylic acid (690 mg, 1.85 mmol) 2-ethyl ester was dissolved in N, N-dimethylformamide di-fe / f-butyl acetal ( 3.0 mi), and stirred at 80 ° C, for two and a half hours. Additionally, N, N-dimethylformamide differic butyl acetal (2.0 ml) was added and stirred at 80 ° C for three hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (150 ml) and water (75 ml). The organic layer was isolated, washed with water and a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate = 25/1 to 5/1) to give the 5-fe / f-butyl ester 2-ethyl ester of acid 1- (toluene-4 -sulfonyl) -1H-indole-2,5-dicarboxylic (551 mg, 69%).
15 1H-RMN (DMSO-De) 8: 8.25 (1H, d, J = 1.4 Hz), 8.12 (1H, d, J = 8.8 Hz), 8.00 (1H, dd, J = 8.8, 1.4 Hz), 7.88 (2H, d, J = 8.0 Hz), 7.48 (1H, s), 7.43 (2H, d, J = 8.0 Hz), 4.37 (2H, q, J = 7.2 Hz), 2.37 (3H, s), 1.56 (9H, s), 1.34 (3H, t, J = 7.2 Hz)15 1H-NMR (DMSO-De) 8: 8.25 (1H, d, J = 1.4 Hz), 8.12 (1H, d, J = 8.8 Hz), 8.00 (1H, dd, J = 8.8, 1.4 Hz), 7.88 (2H, d, J = 8.0 Hz), 7.48 (1H, s), 7.43 (2H, d, J = 8.0 Hz), 4.37 (2H, q, J = 7.2 Hz), 2.37 (3H, s), 1.56 (9H, s), 1.34 (3H, t, J = 7.2 Hz)
ESI (LC-MS modo positivo) m/z 444 [(M+H)+]ESI (LC-MS positive mode) m / z 444 [(M + H) +]
Etapa 17: Síntesis de [5-amino-1-(2-metll-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-¡l]-[1-(tolueno-4-sulfonil)-5-Stage 17: Synthesis of [5-amino-1- (2-metll-1H-benzimdazol-5-yl) -1H-pyrazol-4-yl] - [1- (toluene-4-sulfonyl) -5-
20 trimetilsilaniletinil-1 H-indol-2-il] metanona (1378)20 trimethylsilaniletinyl-1 H-indol-2-yl] methanone (1378)
55
1010
15fifteen
20twenty
2525
3030
[5-Amino-1 -(2-met¡l-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[5-bromo-1 -(tolueno-4 -sulfonil)-1H-¡ndol-2-¡l]-metanona (150 mg), dicloro-bis(trifenilfosfina)paladio (ll)(54 mg), yoduro de cobre(l) (10 mg), trimetilamina (0.7 mi), y N,N- dimetilformamida (DMF) anhidra (0.7 mi) se combinaron juntos en un recipiente a prueba de presión, y se le adicionó trimetilsilil acetileno (150 mg). La mezcla se agitó de 80 a 85°C, bajo nitrógeno, durante 15 horas. Después de enfriar a temperatura ambiente, la mezcla de reacción se diluyó con acetato de etilo, se lavó con una solución acuosa saturada de cloruro de sodio, y se secó sobre sulfato de sodio anhidro. El desecante se eliminó por filtración. El filtrado se concentró bajo presión reducida. El residuo resultante se purificó por cromatografía de columna de sílica gel (metanol/diclorometano = 0/100 a 20/100) para dar la [5-amino-1-(2-metil-1H-bencimidazol-5-¡l)-1H-pirazol- 4-il]- [1-(tolueno-4-sulfon¡l)-5-tr¡met¡l-s¡lan¡let¡n¡l-1H-¡ndol-2-¡l]-metanona (65 mg, 42%).[5-Amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [5-bromo-1 - (toluene-4-sulfonyl) -1H -¡Ndol-2-¡] -methanone (150 mg), dichloro-bis (triphenylphosphine) palladium (ll) (54 mg), copper iodide (l) (10 mg), trimethylamine (0.7 ml), and N Anhydrous N-dimethylformamide (DMF) (0.7 ml) was combined together in a pressure-proof vessel, and trimethylsilyl acetylene (150 mg) was added. The mixture was stirred at 80 to 85 ° C, under nitrogen, for 15 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol / dichloromethane = 0/100 to 20/100) to give the [5-amino-1- (2-methyl-1H-benzimidazol-5-l) - 1H-pyrazol- 4-yl] - [1- (toluene-4-sulfon¡l) -5-tr¡met¡ls¡lan¡let¡n¡l-1H-¡ndol-2-¡l] -methanone (65 mg, 42%).
1H-RMN (DMSO-D6) 6: 12.48 (1H, d, J = 8.4 Hz), 8.04-7.95 (3H, m), 7.80 (1H, s), 7.75 (1H, d, J = 3.7 Hz), 7.69-7.62 (1H, m), 7.62-7.54 (1H, m), 7.50 (1H, dd, J = 8.7, 1.7 Hz), 7.44 (2H, d, J = 8.6 Hz), 7.29 (1H, t, J = 7.9 Hz), 7.20 (1H, s), 7.09-6.97 (2H, m), 2.54 (3H, s), 2.36 (3.0H, s), 0.23 (9.0H, s)1H-NMR (DMSO-D6) 6: 12.48 (1H, d, J = 8.4 Hz), 8.04-7.95 (3H, m), 7.80 (1H, s), 7.75 (1H, d, J = 3.7 Hz), 7.69-7.62 (1H, m), 7.62-7.54 (1H, m), 7.50 (1H, dd, J = 8.7, 1.7 Hz), 7.44 (2H, d, J = 8.6 Hz), 7.29 (1H, t, J = 7.9 Hz), 7.20 (1H, s), 7.09-6.97 (2H, m), 2.54 (3H, s), 2.36 (3.0H, s), 0.23 (9.0H, s)
ESI (LC-MS modo positivo) m/z 607 [(M+H)+]ESI (LC-MS positive mode) m / z 607 [(M + H) +]
Síntesis del éster etílico del ácido 1-bencenosulfon¡l-4-trimetil-silaniletinil- 1H-indol-2-carboxíl¡co (1379)Synthesis of 1-benzenesulfonyl-4-trimethyl-silanyletinyl-1H-indole-2-carboxylic acid ethyl ester (1379)
El éster etílico del ácido 1 -bencenosulfonil-4-trimetil-silaniletinil- 1H-lndol-2-carboxílico se sintetizó por el mismo método como en la Etapa 17.The 1-benzenesulfonyl-4-trimethyl-silanyletinyl-1H-lndol-2-carboxylic acid ethyl ester was synthesized by the same method as in Step 17.
ESI (LC-MS modo positivo) m/z 426 [(M+H)+jESI (LC-MS positive mode) m / z 426 [(M + H) + j
Etapa 18: Síntesis de la N-[2-[5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-carbonil]-1-(tolueno-4-sulfonil)- 1H-indol-6-il]-metanosulfonamida (1380)Stage 18: Synthesis of N- [2- [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-carbonyl] -1- (toluene-4-sulfonyl) - 1H-indole-6-yl] -methanesulfonamide (1380)
La [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-yodo-1-(tolueno-4-sulfonil)-1H-indol-2-il]-metanona (80.3 mg, 0.126 mmol), yoduro de cobre(l) (37.5 mg, 0.197 mmol), metanosulfonamida (37.5 mg, 0.394 mmol), sarcosina (36.2 mg, 0.406 mmol), y trifosfato de potasio (86.0 mg, 9.405 mmol) se disolvieron en 1-metil-2- plrrolldlnona anhidra (0.36 mi), y se calentaron a 140°C con agitación bajo una atmósfera de argón, durante 30 minutos. La mezcla de reacción se adicionó gota a gota a una solución acuosa (20 mi) de cloruro de amonio al 20%, y se extrajo con acetato de etilo, la capa orgánica se lavó con una solución acuosa de cloruro de sodio al 20% y se secó sobre sulfato de sodio anhidro. El desecante se eliminó por filtración. El filtrado se concentró bajo presión reducida, y el residuo resultante se purificó por cromatografía de columna de amino gel (diclorometano/metanol = 15/1) para dar la N-[2-[5-am¡no-1-(2-met¡l-1H-benc¡m¡dazol-5-il)-1H-p¡razol-4-carbonil]-1-(tolueno-4-sulfonil)-1H-indol-[5-Amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [6-iodo-1- (toluene-4-sulfonyl) -1H-indole- 2-yl] -methanone (80.3 mg, 0.126 mmol), copper iodide (l) (37.5 mg, 0.197 mmol), methanesulfonamide (37.5 mg, 0.394 mmol), sarcosine (36.2 mg, 0.406 mmol), and potassium triphosphate (86.0 mg, 9,405 mmol) were dissolved in anhydrous 1-methyl-2-plrrolldlnone (0.36 ml), and heated at 140 ° C with stirring under an argon atmosphere, for 30 minutes. The reaction mixture was added dropwise to an aqueous solution (20 ml) of 20% ammonium chloride, and extracted with ethyl acetate, the organic layer was washed with a 20% aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by amino gel column chromatography (dichloromethane / methanol = 15/1) to give the N- [2- [5-amine-1- (2- Methyl-1H-benzyldazol-5-yl) -1H-p¡razol-4-carbonyl] -1- (toluene-4-sulfonyl) -1H-indole-
6-il] metanosulfonamida como un material amorfo de color amarillo (17.9 mg con un rendimiento del 24%).6-yl] methanesulfonamide as a yellow amorphous material (17.9 mg with a 24% yield).
1H-RMN (DMSO-De) 8: 12.47 (1H, s), 9.93 (1H, brs), 7.97 (1H, s), 7.94 (2H, d, J = 7.9 Hz), 7.77 (1H, s), 7.64-7.59 (3H, m), 7.43 (2H, d, J = 6.7 Hz), 7.29 (1H, d, J = 7.9 Hz), 7.22-7.15 (2H, t, J = 5.2 Hz), 7.01 (2H, brs), 2.97 (3H, s), 2.53 (3H, s), 2.35 (3H, s)1H-NMR (DMSO-De) 8: 12.47 (1H, s), 9.93 (1H, brs), 7.97 (1H, s), 7.94 (2H, d, J = 7.9 Hz), 7.77 (1H, s), 7.64-7.59 (3H, m), 7.43 (2H, d, J = 6.7 Hz), 7.29 (1H, d, J = 7.9 Hz), 7.22-7.15 (2H, t, J = 5.2 Hz), 7.01 (2H , brs), 2.97 (3H, s), 2.53 (3H, s), 2.35 (3H, s)
ESI (LC-MS modo positivo) m/z 604 [(M+H)+]ESI (LC-MS positive mode) m / z 604 [(M + H) +]
5 [Ejemplo 200: Síntesis de [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-(6-metanosulfonilo-1H-indol- 2- ¡l)-metanona]5 [Example 200: Synthesis of [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - (6-methanesulfonyl-1H-indole- 2- 1 ) -metanone]
La [5-amino-1 -(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-(6-metil-sulfanil-1 H -indol-2-il)-metanona (23 mg, 0.057 mmol) se disolvió en trifluoroetanol (5 mi), y se le adicionó una solución acuosa (0.5 mi) de oxona (105 mg, 0.171 10 mmol). La mezcla se agitó a temperatura ambiente bajo una atmósfera de nitrógeno, durante 1.75 horas. La mezcla de reacción se filtró, y el filtrado se concentró. El residuo resultante se purificó por cromatografía de columna de amino gel (diclorometano/metanol = 99/1 a 92/8). De este modo, se obtuvo la [5-amino-1-(2-metil-1H-bencimidazol- 5-¡l)-1 H-pirazol-4-il]-(6-metanosulfonilo-1 H-indol-2-il)-metanona como un sólido de color amarillo pálido (8 mg, 32%).[5-Amino-1 - (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - (6-methyl-sulfanyl-1 H -indole-2-yl) - Methanone (23 mg, 0.057 mmol) was dissolved in trifluoroethanol (5 mL), and an aqueous solution (0.5 mL) of oxone (105 mg, 0.171 mmol) was added. The mixture was stirred at room temperature under a nitrogen atmosphere, for 1.75 hours. The reaction mixture was filtered, and the filtrate was concentrated. The resulting residue was purified by amino gel column chromatography (dichloromethane / methanol = 99/1 to 92/8). Thus, [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H-pyrazol-4-yl] - (6-methanesulfonyl-1 H-indole-2) was obtained -il) -methanone as a pale yellow solid (8 mg, 32%).
1H-RMN (DMSO-D6) 8: 12.48 (1H, d, J = 4.9 Hz), 12.33 (1H, s), 8.35 (1H, d, J = 4.9 Hz), 8.05 (1H, s), 7.94 (1H, d, J = 15 8.5 Hz), 7.65-7.59 (4H, m), 7.31-7.27 (1H, m), 7.11 (2H, d, J = 21.4 Hz), 3.22 (3H, s), 2.54 (3H, s)1H-NMR (DMSO-D6) 8: 12.48 (1H, d, J = 4.9 Hz), 12.33 (1H, s), 8.35 (1H, d, J = 4.9 Hz), 8.05 (1H, s), 7.94 ( 1H, d, J = 15 8.5 Hz), 7.65-7.59 (4H, m), 7.31-7.27 (1H, m), 7.11 (2H, d, J = 21.4 Hz), 3.22 (3H, s), 2.54 ( 3H, s)
ESI (LC-MS modo positivo) m/z 435 [(M+H)+]ESI (LC-MS positive mode) m / z 435 [(M + H) +]
Etapa 19: Síntesis del áster metílico del ácido 6-ciclopropil-1-(tolueno-4-sulfoníl)-1H-indol-2-carboxílico (1381)Stage 19: Synthesis of 6-cyclopropyl-1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid methyl ester (1381)
Cantidades predeterminadas de áster metílico del ácido 6-bromo-1-(tolueno-4-sulfonil)-1H-indol-2-carboxílico (300 20 mg, 0.73 mmol), acetato de paladio (16.5 mg, 0.07 mmol), bís(1,1-dimetiletil)fenilfosfina (0.028 mi, 0.12 mmol), potasio ciclopropil trifluoro borato (163 mg, 1.1 mmol), y carbonato de cesio (718 mg, 2.2 mmol) se colocaron en un recipiente de reacción, y se le adicionaron tolueno (5 mi) y agua (0.5 mi). A continuación, la mezcla resultante se agitó a 100°C, durante 14 horas. Después de enfriarla a temperatura ambiente, la mezcla se diluyó con acetato de etilo, y se lavó dos veces con agua, y a continuación se secó sobre sulfato de sodio anhidro. El desecante se eliminó 25 por filtración, y se llevó a cabo la concentración. A continuación, el residuo obtenido mediante concentración bajo presión reducida se purificó por cromatografía de columna de sílica gel (hexano/acetato de etilo = 97/3 a 7/3). De este modo, se obtuvo un sólido de color amarillo (208 mg, 77%).Default amounts of 6-bromo-1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid methyl ester (300 20 mg, 0.73 mmol), palladium acetate (16.5 mg, 0.07 mmol), bís ( 1,1-dimethylethyl) phenylphosphine (0.028 ml, 0.12 mmol), potassium cyclopropyl trifluoro borate (163 mg, 1.1 mmol), and cesium carbonate (718 mg, 2.2 mmol) were placed in a reaction vessel, and added toluene (5 mi) and water (0.5 mi). Then, the resulting mixture was stirred at 100 ° C for 14 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, and washed twice with water, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the concentration was carried out. Then, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate = 97/3 to 7/3). In this way, a yellow solid (208 mg, 77%) was obtained.
1H-RMN (DMSO-De) 8: 7.82-7.80 (2H, m), 7.68 (1H, brs), 7.52 (1H, d, J = 8.2 Hz), 7.42-7.39 (2H, m), 7.32 (1H, d, J = 0.8 Hz), 7.00 (1H, dd, J = 8.3, 1.5 Hz), 3.83 (3H, s), 2.33 (3H, s), 2.11-2.09 (1H, m), 1.03 (2H, ddd, J = 9.6, 5.2, 3.1 30 Hz), 0.73-0.70 (2H, m)1H-NMR (DMSO-De) 8: 7.82-7.80 (2H, m), 7.68 (1H, brs), 7.52 (1H, d, J = 8.2 Hz), 7.42-7.39 (2H, m), 7.32 (1H , d, J = 0.8 Hz), 7.00 (1H, dd, J = 8.3, 1.5 Hz), 3.83 (3H, s), 2.33 (3H, s), 2.11-2.09 (1H, m), 1.03 (2H, ddd, J = 9.6, 5.2, 3.1 30 Hz), 0.73-0.70 (2H, m)
ESI (LC-MS modo positivo) m/z 370[(M+H)+]ESI (LC-MS positive mode) m / z 370 [(M + H) +]
Los compuestos de los números 1382 a 1384 enumerados en la Tabla 19, se sintetizaron como se describe en la Etapa 19.The compounds of Nos. 1382 to 1384 listed in Table 19, were synthesized as described in Step 19.
Tabla 19Table 19
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1382 1382
- éster metílico del ácido 6-butil-1 -(tolueno-4-sulfonil) -1 H-indol- 2-carboxíllco 386 6-Butyl-1 - (toluene-4-sulfonyl) -1 H-indole-2-carboxylic acid methyl ester 386
- 1383 1383
- $ éster etílico del ácido 5-ciclopropil-1-(tolueno-4-sulfonil)-1H- indol-2-carboxílico 384 5-Cyclopropyl-1- (toluene-4-sulfonyl) -1H- indole-2-carboxylic acid ethyl ester 384
- 1384 1384
- $ 0x3^ éster etílico del ácido 5-bencil-1-(tolueno-4-sulfonil)-1H-indol- 2-carboxílico 434 0x3 ^ 5-benzyl-1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid ethyl ester 434
5 Etapa 20: Síntesis del éster etílico del ácido 5-imidazol-1-il-1H-indol-2-carboxílico (1385)5 Stage 20: Synthesis of 5-imidazol-1-yl-1H-indole-2-carboxylic acid ethyl ester (1385)
[Método de síntesis basado en hidrazona] Síntesis del éster etílico del ácido 2-[(E)-4-im¡dazol-1-il-fenilimino]-[Hydrazone-based synthesis method] Synthesis of 2 - [(E) -4-imdazol-1-yl-phenylimino acid ethyl ester] -
propiónicopropionic
Se disolvió la 4-imidazol-1-il-fenil amina (637 mg) en ácido clorhídrico 2 M/MeOH (3 mi), y este se concentró bajo 10 presión reducida. El residuo se suspendió en ácido clorhídrico concentrado (1 mi), y se adicionó gota a gota a esta una solución acuosa de nitrito de sodio (304 mg, 2.5 mi) durante 30 minutos a 0°C en hielo. La mezcla de reacción se adicionó lentamente gota a gota a una solución acuosa preparada de antemano a partir de soluciones acuosas de hidrosulfito de sodio (2.3 g, 13 mi) e hidróxído de sodio 5 M (400 jxl), mientras se mantenía la temperatura de la mezcla de reacción a 5°C o menos. A continuación, la mezcla se agitó a 25°C, durante una hora. Se adicionó gota a 15 gota una solución en etanol (5 mi) de piruvato de etilo (465 mi) a la mezcla de reacción. Después de agitar a 50°C, durante 30 minutos, la mezcla se agitó adicionalmente a 25°C, durante 10 horas. El pH de la mezcla se ajustó a 11 utilizando una solución acuosa (aproximadamente 10 mi) de fosfato de potasio al 20%. El precipitado resultante se recolectó por filtración, y se secó. De este modo, se obtuvo el éster etílico del ácido 2-[(E)-4-imidazol-1-il-fenilimino]- propiónico como un polvo de color amarillo pálido (1.1 g, 99%).4-Imidazol-1-yl-phenyl amine (637 mg) was dissolved in 2M hydrochloric acid / MeOH (3 mL), and this was concentrated under reduced pressure. The residue was suspended in concentrated hydrochloric acid (1 ml), and an aqueous solution of sodium nitrite (304 mg, 2.5 ml) was added dropwise thereto for 30 minutes at 0 ° C on ice. The reaction mixture was slowly added dropwise to an aqueous solution prepared beforehand from aqueous solutions of sodium hydrosulfite (2.3 g, 13 ml) and 5 M sodium hydroxide (400 jxl), while maintaining the temperature of the reaction mixture at 5 ° C or less. Then, the mixture was stirred at 25 ° C for one hour. A solution in ethanol (5 ml) of ethyl pyruvate (465 ml) was added dropwise to the reaction mixture. After stirring at 50 ° C, for 30 minutes, the mixture was further stirred at 25 ° C, for 10 hours. The pH of the mixture was adjusted to 11 using an aqueous solution (approximately 10 ml) of 20% potassium phosphate. The resulting precipitate was collected by filtration, and dried. Thus, the 2 - [(E) -4-imidazol-1-yl-phenylimino] -propionic acid ethyl ester was obtained as a pale yellow powder (1.1 g, 99%).
20 [Método de síntesis basado en indol]20 [Indole-based synthesis method]
Síntesis del éster etílico del ácido 5-imldazol-1 -II- 1H-¡ndol-2-carboxílicoSynthesis of 5-imldazol-1-II-1H-landol-2-carboxylic acid ethyl ester
Se adicionó éster etílico del ácido 2-[(E)-4-lmidazol-1-il-fenilimino]-propiónico (842 mg) a un reactivo de Eaton (4 mi), y esta se agitó a 100°C, durante una hora. Después de ajustar el pH de la mezcla de reacción a 11 utilizando una solución acuosa (aproximadamente 10 mi) de fosfato de potasio al 20%, la mezcla se extrajo con acetato de etilo (30 5 mi). La capa orgánica se lavó con una solución acuosa saturada con cloruro de sodio (20 mi), y la capa orgánica se concentró bajo presión reducida. El residuo resultante se purificó por cromatografía de columna de sílica gel (diclorometano/metanol). De este modo, se obtuvo el éster etílico del ácido 5-imidazol-1-il-1H-indol-2-carboxílico como un material amorfo de color amarillo (370 mg, 47%).2 - [(E) -4-lmidazol-1-yl-phenylimino] -propionic acid ethyl ester (842 mg) was added to an Eaton reagent (4 ml), and it was stirred at 100 ° C for one hour. After adjusting the pH of the reaction mixture to 11 using an aqueous solution (approximately 10 ml) of 20% potassium phosphate, the mixture was extracted with ethyl acetate (30 ml). The organic layer was washed with an aqueous solution saturated with sodium chloride (20 ml), and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol). Thus, the 5-imidazol-1-yl-1H-indole-2-carboxylic acid ethyl ester was obtained as a yellow amorphous material (370 mg, 47%).
ESI (LC-MS modo positivo) m/z 256[(M+H)+]ESI (LC-MS positive mode) m / z 256 [(M + H) +]
10 Los compuestos de los números 1386 a 1394 enumerados en la Tabla 20, se sintetizaron como se describe en la Etapa 20.The compounds of numbers 1386 to 1394 listed in Table 20, were synthesized as described in Step 20.
Tabla 20Table 20
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1386 1386
- CtH, s éster etílico del ácido 4-tert-butil-1H-lndol-2-carboxílico 246 CtH, 4-tert-butyl-1H-lndol-2-carboxylic acid ethyl ester 246
- 1387 1387
- éster etílico del ácido 5-trifluoromet¡lsulfanil-1H-indol-2- carboxíllco 290 5-Trifluorometlsulfanyl-1H-indole-2-carboxylic acid ethyl ester 290
- 1388 1388
- F éster etílico del ácido 5-trifluorometllsulfan¡l-1 H-indol-2- carboxílico 274 [M- H] 5-Trifluorometllsulfan¡l-1 H-indole-2-carboxylic acid ethyl ester 274 [M- H]
- 1389 1389
- éster etílico del ácido 5-fIuoro-4-trifluorometiI-1 H-lndol-2- carboxílico 274 [M- H] 5-fIuoro-4-trifluorometiI-1 H-lndol-2-carboxylic acid ethyl ester 274 [M- H]
- 1390 1390
- Vlv éster etílico del ácido 6-tert-butil-1H-¡ndol-2-carboxíl¡co 246 Vlv 6-tert-butyl-1H-α-2-carboxylic acid ethyl ester 246
- 1391 1391
- éster etílico del ácido 4,6-dimetil-1 H-indol-2-carboxílico 218 4,6-Dimethyl-1 H-indole-2-carboxylic acid ethyl ester 218
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1392 1392
- ycxk, éster etílico del ácido 5-tert-butil-1 H-indol-2-carboxílico 246 ycxk, 5-tert-butyl-1 H-indol-2-carboxylic acid ethyl ester 246
- 1393 1393
- éster etílico del ácido 5-isopropil-1 H-indol-2-carboxílico 232 5-Isopropyl-1 H-indole-2-carboxylic acid ethyl ester 232
- 1394 1394
- éster etílico del ácido 5-fenoxi-1H-indol-2-carboxílico 282 5-phenoxy-1H-indole-2-carboxylic acid ethyl ester 282
Etapa 21: Síntesis de 1-cloro-2-cicloprop¡lmetox¡-4-n¡tro-benceno (1395)Stage 21: Synthesis of 1-Chloro-2-cycloprop¡lmethox¡-4-n¡tro-benzene (1395)
5 Se adicionó bromuro de ciclopropilmetilo (2.0 mi, 20 mmol, 2.0 eq.) a una solución de la mezcla de 2-cloro-5- nitrofenol (1.7 g, 10 mmol), carbonato de potasio (2.7 g, 20 mmol), y acetonltrllo anhidro (20 mi). Esto se agitó a 80°C, durante ocho horas. Después de enfriarla a temperatura ambiente, la mezcla de reacción se filtró a través de Celite, y se lavó con acetato de etilo. El filtrado se concentró bajo presión reducida. Esto produjo 1-cloro-2- ciclopropilmetoxl-4-nltro-benceno en bruto como un sólido de color rojo pálido. El producto en bruto se utilizó en 10 reacciones posteriores sin ser purificado.5 Cyclopropylmethyl bromide (2.0 ml, 20 mmol, 2.0 eq.) Was added to a solution of the mixture of 2-chloro-5- nitrophenol (1.7 g, 10 mmol), potassium carbonate (2.7 g, 20 mmol), and anhydrous acetonltrllo (20 ml). This was stirred at 80 ° C for eight hours. After cooling to room temperature, the reaction mixture was filtered through Celite, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure. This produced crude 1-chloro-2- cyclopropylmethoxl-4-nltro-benzene as a pale red solid. The crude product was used in 10 subsequent reactions without being purified.
1H-RMN (DMSO-De) 6: 7.84 (1H, dd, J = 8.4, 2.5 Hz), 7.81 (1H, d, J = 2.5 Hz), 7.74 (1H, d, J = 8.4 Hz), 4.08 (2H, d, J = 7.1 Hz), 1.33-1.23 (1H, m), 0.63-0.59 (2H, m), 0.41-0.37 (2H, m)1H-NMR (DMSO-De) 6: 7.84 (1H, dd, J = 8.4, 2.5 Hz), 7.81 (1H, d, J = 2.5 Hz), 7.74 (1H, d, J = 8.4 Hz), 4.08 ( 2H, d, J = 7.1 Hz), 1.33-1.23 (1H, m), 0.63-0.59 (2H, m), 0.41-0.37 (2H, m)
Etapa 22: Síntesis de 4-cloro-3-ciclopropllmetox¡-fen¡lam¡na (1396)Stage 22: Synthesis of 4-chloro-3-cyclopropllmetox¡-fen¡lam¡na (1396)
15 El 1-cloro-2-ciclopropilmetoxi-4-nitro-benceno (2.3 g, 10 mmol) se disolvió en etanol (30 mi) y agua (30 mi), y a continuación se le adicionó gradualmente ditionito de sodio. Esto se agitó a 80°C, durante cuatro horas y media. Después de enfriarla a temperatura ambiente, se adicionó a la mezcla de reacción una solución acuosa de clorhidrato 5 M (40 mi). Esto se agitó a temperatura ambiente, durante una hora. A continuación, se adicionó una solución acuosa (42 mi) de hidróxido de sodio 5 M, y la solución se alcalinizó y se extrajo con acetato de etilo. El 20 extracto se lavó con agua y una solución acuosa saturada con cloruro de sodio, y se secó sobre sulfato de sodio anhidro. El desecante se eliminó por filtración, y se llevó a cabo la concentración. A continuación, el residuo obtenido mediante concentración bajo presión reducida se purificó por cromatografía de columna de sílica gel. De este modo,The 1-Chloro-2-cyclopropylmethoxy-4-nitro-benzene (2.3 g, 10 mmol) was dissolved in ethanol (30 ml) and water (30 ml), and then sodium dithionite was gradually added. This was stirred at 80 ° C for four and a half hours. After cooling to room temperature, a 5M aqueous solution of hydrochloride (40 ml) was added to the reaction mixture. This was stirred at room temperature, for one hour. Then, an aqueous solution (42 ml) of 5 M sodium hydroxide was added, and the solution was made alkaline and extracted with ethyl acetate. The extract was washed with water and an aqueous solution saturated with sodium chloride, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the concentration was carried out. Then, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography. In this way,
se obtuvo la 4-cloro-3-ciclopropilmetoxi-fenilamina como un material como goma de color amarillo pálido (1.4 g).4-Chloro-3-cyclopropylmethoxy-phenylamine was obtained as a material such as pale yellow gum (1.4 g).
1H-RMN (DMSO-De) 8: 6.95 (1H, d, J = 8.3 Hz), 6.28 (1H, d, J = 2.4 Hz), 6.11 (1H, dd, J = 8.3, 2.4 Hz), 5.19 (2H, s), 25 3.76 (2H, d, J = 7.1 Hz), 1.24-1.18 (1H, m), 0.59-0.54 (2H, m), 0.35-0.30 (2H, m)1H-NMR (DMSO-De) 8: 6.95 (1H, d, J = 8.3 Hz), 6.28 (1H, d, J = 2.4 Hz), 6.11 (1H, dd, J = 8.3, 2.4 Hz), 5.19 ( 2H, s), 25 3.76 (2H, d, J = 7.1 Hz), 1.24-1.18 (1H, m), 0.59-0.54 (2H, m), 0.35-0.30 (2H, m)
ESI (LC-MS modo positivo) m/z 198, 200 [(M+H)+]ESI (LC-MS positive mode) m / z 198, 200 [(M + H) +]
Etapa 23: Síntesis de 4-bromo-2-yodo-5-trifluorometil-fenilamina (1397)Step 23: Synthesis of 4-bromo-2-iodo-5-trifluoromethyl-phenylamine (1397)
Se adicionó gradualmente yodo (1.4 g, 5.5 mmol, 1.1 eq.) a una solución de la mezcla de 4-bromo-3-tr¡fluorometil 5 anilina (1.2 g, lOmmol), sulfato de plata (1.72 g, 5.5 mmol, 1.1 eq.), y etanol anhidro (35 mi). Esta se agitó a temperatura ambiente durante dos horas y media. La mezcla de reacción se filtró a través de Celite, y se lavó con acetato de etilo. La solución de lavado se lavó con soluciones acuosas de tiosulfato de sodio al 10%, bicarbonato de sodio saturado, y cloruro de sodio saturado, y a continuación se secó sobre sulfato de sodio anhidro. El desecante se eliminó por filtración, y se llevó a cabo la concentración. Se obtuvo 4-bromo-2-yodo-5-tr¡fluorometil-fen¡lam¡na 10 sólido, crudo mediante concentración bajo presión reducida. El producto en bruto resultante se utilizó en reacciones posteriores sin ser purificado.Iodine (1.4 g, 5.5 mmol, 1.1 eq.) Was gradually added to a solution of the mixture of 4-bromo-3-trifluoromethyl 5 aniline (1.2 g, 10mmol), silver sulfate (1.72 g, 5.5 mmol, 1.1 eq.), And anhydrous ethanol (35 ml). This was stirred at room temperature for two and a half hours. The reaction mixture was filtered through Celite, and washed with ethyl acetate. The wash solution was washed with aqueous solutions of 10% sodium thiosulfate, saturated sodium bicarbonate, and saturated sodium chloride, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the concentration was carried out. Solid, crude 4-bromo-2-iodo-5-trifluoromethyl-phenylamine was obtained by concentration under reduced pressure. The resulting crude product was used in subsequent reactions without being purified.
1H-NNM(DMSO-De) 8: 7.94 (1H, s), 7.15(11-1, s), 5.86 (2H, s)1H-NNM (DMSO-De) 8: 7.94 (1H, s), 7.15 (11-1, s), 5.86 (2H, s)
ESI (LC-MS modo positivo) m/z 366, 368 [(M+H)+]ESI (LC-MS positive mode) m / z 366, 368 [(M + H) +]
Los compuestos de los números 1398 a 1402 enumerados en la Tabla 21, se sintetizaron como se describe en la 15 Etapa 23.The compounds of Nos. 1398 to 1402 listed in Table 21, were synthesized as described in Step 23.
Tabla 21Table 21
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1398 1398
- rxx,~ 5-bromo-4-fluoro-2-yodo-fenilamina 316, 318 rxx, ~ 5-bromo-4-fluoro-2-iodo-phenylamine 316, 318
- 1399 1399
- FywNH, 4-bromo-5-fluoro-2-yodo-fenilamina 316, 318 FywNH, 4-bromo-5-fluoro-2-iodo-phenylamine 316, 318
- 1400 1400
- wr 2,2-difluoro-6-yodo-benzo [1,3]dioxol-5-ilamina 300 wr 2,2-difluoro-6-iodo-benzo [1,3] dioxol-5-ylamine 300
- 1401 1401
- CiA^s.| 4-cloro-5-ciclopropilmetoxi-2-iodofenilamina 324, 326 CiA ^ s. | 4-Chloro-5-cyclopropylmethoxy-2-iodophenylamine 324, 326
- 1402 1402
- 4-bromo-2-yodo-5-metoxi-fenilamina 3281, 330 4-Bromo-2-iodo-5-methoxy-phenylamine 3281, 330
Etapa 24: Síntesis de N-(4-bromo-2-yodo-5-trifluoromet¡l-fen¡l)-4-met¡l bencenosulfonamlda (1403)Step 24: Synthesis of N- (4-bromo-2-iodo-5-trifluoromethyl-phenol) -4-methylbenzenesulfonamide (1403)
Se disolvieron 4 -bromo-2-yodo-5-tr¡fluoromet¡l-fenilamina (366 mg, 1.0 mmol) y p-tolueno sulfonil cloruro (286 mg, 1.5 mmol, 1.5 eq.) en piridina anhidra (2.5 mi). Esta se agitó a temperatura ambiente, durante 16 horas. Una solución acuosa de hidróxido de sodio 1 M se adicionó a la mezcla de reacción, y esta se agitó, durante cinco minutos. La 5 mezcla de reacción se diluyó con acetato de etilo. La capa orgánica se aisló, y se lavó con una solución acuosa de ácido clorhídrico 1 M y una solución acuosa saturada con cloruro de sodio, y se secó sobre sulfato de sodio anhidro. El desecante se eliminó por filtración, y se llevó a cabo la concentración. A continuación, el residuo obtenido mediante concentración bajo presión reducida se disolvió en tetrahidrofurano (THF) (2.5 mi), y a continuación una solución en tetrahidrofurano (THF) de fluoruro de tetrabutllamonio 1M se le adicionó. Esto se agitó a temperatura 10 ambiente, durante 17 horas. La mezcla de reacción se diluyó con acetato de etilo. La capa orgánica se aisló, y se lavó con agua y una solución acuosa saturada con cloruro de sodio, y a continuación se secó sobre sulfato de sodio anhidro. El desecante se eliminó por filtración y se llevó a cabo la concentración. A continuación, el residuo obtenido mediante concentración bajo presión reducida se purificó por cromatografía de columna de síllca gel. De este modo, se obtuvo N-(4-bromo-2-yodo-5-trifluorometil-fenll)-4-met¡l bencenosulfonamlda como un sólido de color marrón 15 pálido (494 mg, rendimiento de tres etapas del 95%).4-Bromo-2-iodo-5-trifluoromethyl-phenylamine (366 mg, 1.0 mmol) and p-toluene sulfonyl chloride (286 mg, 1.5 mmol, 1.5 eq.) Were dissolved in anhydrous pyridine (2.5 ml) . This was stirred at room temperature for 16 hours. A 1 M aqueous solution of sodium hydroxide was added to the reaction mixture, and it was stirred for five minutes. The reaction mixture was diluted with ethyl acetate. The organic layer was isolated, and washed with an aqueous solution of 1 M hydrochloric acid and an aqueous solution saturated with sodium chloride, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the concentration was carried out. Then, the residue obtained by concentration under reduced pressure was dissolved in tetrahydrofuran (THF) (2.5 ml), and then a solution in tetrahydrofuran (THF) of 1M tetrabutylammonium fluoride was added. This was stirred at room temperature for 17 hours. The reaction mixture was diluted with ethyl acetate. The organic layer was isolated, and washed with water and an aqueous solution saturated with sodium chloride, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration and the concentration was carried out. Then, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography. Thus, N- (4-bromo-2-iodo-5-trifluoromethyl-fenll) -4-methylbenzenesulfonamide was obtained as a pale brown solid (494 mg, three-stage yield of 95%) .
1H-RMN (DMSO-De) 8: 10.10 (1H, s), 8.34 (1H, s), 7.58 (2H, d, J = 8.2 Hz), 7.39 (2H, d, J = 8.2 Hz), 7.27 (1H, s), 2.38 (3H, s)1H-NMR (DMSO-De) 8: 10.10 (1H, s), 8.34 (1H, s), 7.58 (2H, d, J = 8.2 Hz), 7.39 (2H, d, J = 8.2 Hz), 7.27 ( 1H, s), 2.38 (3H, s)
ESI (LC-MS modo positivo) m/z 520, 522 [(M+H)+jESI (LC-MS positive mode) m / z 520, 522 [(M + H) + j
Los compuestos de los números 1404 a 1408 enumerados en la Tabla 22, se sintetizaron como se describe en la 20 Etapa 24.The compounds of numbers 1404 to 1408 listed in Table 22, were synthesized as described in Step 24.
Tabla 22Table 22
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1404 1404
- $ C- ,xx N-(5-bromo-4-fluoro-2-yodofenll)-4- metilbencenosulfonamlda 470, 472 $ C-, xx N- (5-bromo-4-fluoro-2-iodophenyl) -4- methylbenzenesulfonamlda 470, 472
- 1405 1405
- ;xxr N-(4-bromo-5-fluoro-2-yodofenll)-4- metilbencenosulfonamlda No se observa ; xxr N- (4-bromo-5-fluoro-2-iodophenll) -4- methylbenzenesulfonamlda Not observed
- 1406 1406
- $ ^xxr N-(2,2-difluoro-6-yodo-benzo [1,3]dioxol-5-il )-4- metilbencenosulfonamlda 454 xxr N- (2,2-difluoro-6-iodo-benzo [1,3] dioxol-5-yl) -4- methylbenzenesulfonamide 454
- Compuesto No. Compound No.
- Estructura Nombre del compuesto miz Structure Name of compound miz
- 1407 1407
- N-(4-cloro-5-cicloprop¡lmetox¡-2-yodofen¡l)-4- metll- bencenosulfonamida 478, 480 N- (4-Chloro-5-cyclopropylmethox¡-2-iodophenol) -4- metll-benzenesulfonamide 478, 480
- 1408 1408
- $ lx£ N-(4-bromo-2-yodo-5-metoxi-fen¡l)-4- metilbencenosulfonamida 482, 484 lx £ N- (4-bromo-2-iodo-5-methoxy-phenol) -4- methylbenzenesulfonamide 482, 484
Etapa 25: Síntesis del éster etílico del ácido 5-bromo-1-(tolueno-4-sulfonil)-6-trifluorometil- 1H-lndol-2-carboxíl¡co (1409)Step 25: Synthesis of the 5-bromo-1- (toluene-4-sulfonyl) -6-trifluoromethyl-1H-lndol-2-carboxylic acid ethyl ester (1409)
5 Se adicionaron N,N-diisopropiletil amina (0.42 mi, 2.4 mmol), propionato de etilo (0.12 mi, 1.2 mmol), y tetrakis(trifenilfosfina) paladio (46 mg, 0.04 mmol) a una solución en tetrahidrofurano (THF) anhidro (3.2 mi) que contienen N-(4-bromo-2-yodo-5-trifluorometil-fenil)-4-metil-bencenosulfonamida (208 mg, 0.4 mmol) y bromuro de zinc (270 mg, 1.2 mmol). A continuación, la mezcla se evacuó, y rellenó con argón. Esta se agitó a 80°C, durante 13 horas. Después de enfriarla a temperatura ambiente, la mezcla de reacción se filtró a través de Celite, y se lavó con 10 acetato de etilo. La solución de lavado se lavó con una solución acuosa saturada con bicarbonato de sodio y una solución acuosa saturada con cloruro de sodio, y se secó sobre sulfato de sodio anhidro. El desecante se eliminó por filtración, y se llevó a cabo la concentración. A continuación, el residuo obtenido mediante concentración bajo presión reducida se purificó por cromatografía de columna de sí Mea gel. De este modo, se obtuvo el éster etílico del ácido 5-bromo-1-(tolueno-4-sulfon¡l)-6-tr¡fluorometil- 1H-indol-2-carboxílico como un sólido de color marrón pálido 15 (195 mg, 50%).5 N, N-diisopropylethyl amine (0.42 ml, 2.4 mmol), ethyl propionate (0.12 ml, 1.2 mmol), and tetrakis (triphenylphosphine) palladium (46 mg, 0.04 mmol) were added to an anhydrous tetrahydrofuran (THF) solution (3.2 ml) containing N- (4-bromo-2-iodo-5-trifluoromethyl-phenyl) -4-methyl-benzenesulfonamide (208 mg, 0.4 mmol) and zinc bromide (270 mg, 1.2 mmol). Then the mixture was evacuated, and filled with argon. This was stirred at 80 ° C for 13 hours. After cooling to room temperature, the reaction mixture was filtered through Celite, and washed with ethyl acetate. The wash solution was washed with an aqueous solution saturated with sodium bicarbonate and an aqueous solution saturated with sodium chloride, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the concentration was carried out. Then, the residue obtained by concentration under reduced pressure was purified by Mea gel column chromatography. Thus, the 5-bromo-1- (toluene-4-sulfonyl) -6-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester was obtained as a pale brown solid 15 (195 mg, 50%).
1H-RMN (DMSO-De) 8: 8.37 (1H, s), 8.29 (1H, s), 7.89 (2H, d, J = 8.2 Hz), 7.47 (2H, d, J = 8.2 Hz), 7.43 (1H, s), 4.36 (2H, q, J = 7.1 Hz), 2.38 (3H, s), 1.30 (3H, t, J = 7.1 Hz)1H-NMR (DMSO-De) 8: 8.37 (1H, s), 8.29 (1H, s), 7.89 (2H, d, J = 8.2 Hz), 7.47 (2H, d, J = 8.2 Hz), 7.43 ( 1H, s), 4.36 (2H, q, J = 7.1 Hz), 2.38 (3H, s), 1.30 (3H, t, J = 7.1 Hz)
ESI (LC-MS modo positivo) m/z 490, 492 [(M+H)+]ESI (LC-MS positive mode) m / z 490, 492 [(M + H) +]
Los compuestos de los números 1410 a 1414 enumerados en la Tabla 23, se sintetizaron como se describe en la 20 Etapa 25.The compounds of numbers 1410 to 1414 listed in Table 23, were synthesized as described in Step 25.
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1410 1410
- éster etílico del ácido 6-bromo-5-fluoro-1-(tolueno -4- sulfonil)-1H-indol-2-carboxíllco 440,442 6-Bromo-5-fluoro-1- (toluene -4-sulfonyl) -1H-indole-2-carboxylic acid ethyl ester 440,442
- 1411 1411
- éster etílico del ácido 5-bromo-6-fluoro-1 -(tolueno -4- sulfonil)-1H-indol-2-carboxíllco No se observa 5-Bromo-6-fluoro-1 - (toluene -4-sulfonyl) -1H-indole-2-carboxylic acid ethyl ester Not observed
- 1412 1412
- éster etílico del ácido 5-bromo-1-(tolueno-4-sulfonil)-6- trifluorometil -1 H-indol-2-carboxílico 490, 492 5-Bromo-1- (toluene-4-sulfonyl) -6- trifluoromethyl-1-H-indole-2-carboxylic acid ethyl ester 490, 492
- 1413 1413
- éster etílico del ácido 2,2-dlfluoro-5-(tolueno-4-sulfonll)- 5H-[1,3]dloxolo [4,5-f]indol-6-carboxílico 424 2,2-dlfluoro-5- (toluene-4-sulfonll) - 5H- [1,3] dloxolo [4,5-f] indole-6-carboxylic acid ethyl ester 424
- 1414 1414
- éster etílico del ácido 5-cloro-6-ciclopropllmetox¡-1- (tolueno-4- sulfonil)-1 H-indol-2-carboxílico 448, 450 5-Chloro-6-cyclopropllmethox¡-1- (toluene-4-sulfonyl) -1 H-indol-2-carboxylic acid ethyl ester 448, 450
Etapa 26: Síntesis de N-benzh¡drM¡deno-N’-(3,5-d¡-ferí-but¡l-fenil)-h¡drazina (1415)Stage 26: Synthesis of N-benzh¡drM¡deno-N ’- (3,5-d¡-ferí-but¡l-phenyl) -h¡drazina (1415)
5 Acetato de paladio (8.4 mg, 0.037 mmol) y 2-diciclohexilfosf¡no-2’,4’,6’-tr¡-¡-prop¡l-1,1 ’-bifenil (XPHOS) (35.6 mg, 0.074 mmol) se disolvieron en alcohol ferf-amílico (10 jxl, 0.093 mmol) y etilenglicol dimetil éter anhidro (0.25 mi). La mezcla se calentó y se agitó a 60°C, durante cinco minutos bajo una atmósfera de nitrógeno para preparar un catalizador. En un recipiente de reacción separado bajo una atmósfera de nitrógeno, 1-bromo-3,5-di-f-butil benceno (501 mg, 1.9 mmol), litio bis(trimetilsilil) amida (475 mg, 2.8 mmol), y benzofenona hldrazona (401 mg, 2.0 mmol) se 10 disolvieron en etilenglicol dimetil éter anhidro (2.5 mi). A continuación, se le adicionó una solución que contiene el5 Palladium acetate (8.4 mg, 0.037 mmol) and 2-dicyclohexylphosphine-2 ', 4', 6'-tr¡-¡-propyl-1,1 '-biphenyl (XPHOS) (35.6 mg, 0.074 mmol) were dissolved in ferf-amyl alcohol (10 jxl, 0.093 mmol) and ethylene glycol dimethyl ether anhydrous (0.25 ml). The mixture was heated and stirred at 60 ° C for five minutes under a nitrogen atmosphere to prepare a catalyst. In a separate reaction vessel under an atmosphere of nitrogen, 1-bromo-3,5-di-f-butyl benzene (501 mg, 1.9 mmol), lithium bis (trimethylsilyl) amide (475 mg, 2.8 mmol), and benzophenone Hldrazone (401 mg, 2.0 mmol) was dissolved in anhydrous ethylene glycol dimethyl ether (2.5 mL). Next, a solution containing the
catalizador preparado. Después de la desalreación, esta se calentó y se agitó a 90°C, durante dos horas bajo una atmósfera de nitrógeno. La mezcla de reacción se enfrió a temperatura ambiente, y a continuación se concentró bajo presión reducida. El residuo resultante se purificó por cromatografía de columna de sílica gel (hexano/acetato de etilo = 100/5). De este modo, se obtuvo la N-benzhidrilideno-N’-(3,5-di-ferf-butil-fenil)-hidrazina como un material 5 amorfo de color amarillo (699 mg, 97.7%).prepared catalyst After the desalination, it was heated and stirred at 90 ° C, for two hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate = 100/5). Thus, N-benzhydrylidene-N '- (3,5-di-ferf-butyl-phenyl) -hydrazine was obtained as a yellow amorphous material (699 mg, 97.7%).
1H-NNM (DMSO-De) 8: 8.72 (1.0H, s), 7.63-7.53 (3.0H, m), 7.42-7.25 (7.0H, m), 7.11 (2.OH, s), 6.83 (1.0H, s), 1.26 (18.OH, s)1H-NNM (DMSO-De) 8: 8.72 (1.0H, s), 7.63-7.53 (3.0H, m), 7.42-7.25 (7.0H, m), 7.11 (2.OH, s), 6.83 (1.0 H, s), 1.26 (18.OH, s)
ESI (LC-MS modo positivo) m/z 385 [(M+H)+]ESI (LC-MS positive mode) m / z 385 [(M + H) +]
Etapa 27: Síntesis del áster etílico del ácido 4,6-di-fe/f-butil-1H-indol-2-carbónico (1416)Step 27: Synthesis of 4,6-di-fe / f-butyl-1H-indole-2-carbonic acid ethyl ester (1416)
1010
Se disolvió N-Benzhidrilideno-N’-(3,5-di-fert-butil-fenil)-hidrazina (617 mg, 1.6 mmol) en etanol (12 mi). A continuación, se le adicionaron piruvato de etilo (212 jxl, 1.9 mmol) y ácido p-tolueno sulfónico monohidrato (914 mg, 4.8 mmol). Esta se calentó y se agitó a 150°C por microondas bajo una atmósfera de nitrógeno, durante una hora. Después de enfriarla a temperatura ambiente, la mezcla de reacción se combinó con agua y una solución acuosa 15 saturada con bicarbonato de sodio. El producto se extrajo en acetato de etilo. La capa orgánica se aisló, y se lavóN-Benzhydrylidene-N '- (3,5-di-fert-butyl-phenyl) -hydrazine (617 mg, 1.6 mmol) was dissolved in ethanol (12 mL). Then, ethyl pyruvate (212 jxl, 1.9 mmol) and p-toluene sulfonic acid monohydrate (914 mg, 4.8 mmol) were added. This was heated and stirred at 150 ° C by microwave under a nitrogen atmosphere, for one hour. After cooling to room temperature, the reaction mixture was combined with water and an aqueous solution saturated with sodium bicarbonate. The product was extracted in ethyl acetate. The organic layer was isolated, and washed
con una solución acuosa saturada con cloruro de sodio, y se secó sobre sulfato de magnesio. El desecante sewith an aqueous solution saturated with sodium chloride, and dried over magnesium sulfate. The desiccant is
eliminó por filtración, y se llevó a cabo la concentración. A continuación, el residuo obtenido mediante concentración bajo presión reducida se purificó por cromatografía de columna de sílica gel (hexano/acetato de etilo =100/5). De este modo, se obtuvo el éster etílico del ácido 4,6-di-fe/t-butil- 1H-indol-2-carboxílico como un sólido de color marrón 20 (268 mg, 56%).filtered off, and the concentration was carried out. Then, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate = 100/5). Thus, the 4,6-di-fe / t-butyl-1H-indole-2-carboxylic acid ethyl ester was obtained as a brown solid 20 (268 mg, 56%).
1H-RMN (DMSO-De) 8: 11.76 (1.0H, brs), 7.27 (1.0H, s), 7.22-7.22 (1 OH, brm), 7.04-7.03 (1 OH, brm), 4.33 (2.0H, q, J = 7.2 Hz), 1.44 (9.OH, s), 1.36-1.32 (12.0H, m)1H-NMR (DMSO-De) 8: 11.76 (1.0H, brs), 7.27 (1.0H, s), 7.22-7.22 (1 OH, brm), 7.04-7.03 (1 OH, brm), 4.33 (2.0H , q, J = 7.2 Hz), 1.44 (9.OH, s), 1.36-1.32 (12.0H, m)
ESI (LC-MS modo positivo) m/z 302 [(M+H)+jESI (LC-MS positive mode) m / z 302 [(M + H) + j
Etapa 28: Síntesis del éster metílico del ácido 6-(5-fluoro-piridin-2-il)-1-(tolueno-4-sulfonil)-1H-indol-2-carboxílico 25 (1417)Step 28: Synthesis of 6- (5-fluoro-pyridin-2-yl) -1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid methyl ester (1417)
éster metílico del ácido 6-bromo-1-(tolueno-4-sulfoníl)-1H-indol-2-carboxílíco (202.0 mg, 0.495 mmol), diclorobis(trifenilfosfina)paladio (II) (35.6 mg, 0.051 mmol), bís(pinacol)diborano (189.3 mg, 0.745 mmol), acetato de potasio (147.3 mg, 1.51 mmol), y dioxano (1.6 mi) se mezclaron. El aíre se reemplazó tres veces con argón bajo 30 presión reducida. La mezcla se sometió a microondas a 120°C, durante 30 minutos. Se adicionaron diclorobis(trifenilfosfina)paladio (II) (35.6 mg, 0.051 mmol) y 2-bromo-5-fluoro-píríd¡na (206.9 mg, 1.48 mmol) a la mezcla de reacción. Después de la desaireación, el aire se reemplazó tres veces con argón. Esta se calentó y se agitó a 100°C, durante tres horas. La mezcla de reacción se extrajo con acetato de etilo, y el extracto se secó sobre sulfato de sodio anhidro. El desecante se eliminó por filtración, y se llevó a cabo la concentración. A continuación, el 35 residuo obtenido mediante concentración bajo presión reducida se purificó por cromatografía de columna de amino gel (n-hexano/acetato de etilo = 7/100 a 63/100). De este modo, se obtuvo el éster metílico del ácido 6-(5-fluoro-6-Bromo-1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid methyl ester (202.0 mg, 0.495 mmol), dichlorobis (triphenylphosphine) palladium (II) (35.6 mg, 0.051 mmol), bís (pinacol) diborane (189.3 mg, 0.745 mmol), potassium acetate (147.3 mg, 1.51 mmol), and dioxane (1.6 ml) were mixed. The air was replaced three times with argon under reduced pressure. The mixture was microwaved at 120 ° C for 30 minutes. Dichlorobis (triphenylphosphine) palladium (II) (35.6 mg, 0.051 mmol) and 2-bromo-5-fluoropyridine (206.9 mg, 1.48 mmol) were added to the reaction mixture. After deaeration, the air was replaced three times with argon. This was heated and stirred at 100 ° C for three hours. The reaction mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the concentration was carried out. Then, the residue obtained by concentration under reduced pressure was purified by amino gel column chromatography (n-hexane / ethyl acetate = 7/100 to 63/100). In this way, the 6- (5-fluoro-) acid methyl ester was obtained
piridin-2-il)-1-(tolueno-4-sulfonil)-1H-¡ndol-2-carboxílico como un material amorfo de color amarillo pálido (150.5 mg, rendimiento de 72%).pyridin-2-yl) -1- (toluene-4-sulfonyl) -1H-landol-2-carboxylic as a pale yellow amorphous material (150.5 mg, 72% yield).
1H-RMN (CDCI3) 5: 8.70 (1H, s), 8.59 (1H, d, J = 2.7 Hz), 7.93 (3H, d, J = 8.2 Hz), 7.83 (1H, dd, J = 8.8, 3.8 Hz), 7.65 (1H, d, J = 8.2 Hz), 7.53 (1H, td, J = 8.4, 2.9 Hz), 7.29-7.25 (2H, m), 7.19 (1H, s), 3.95 (3H, s), 2.37 (3H, s)1H-NMR (CDCI3) 5: 8.70 (1H, s), 8.59 (1H, d, J = 2.7 Hz), 7.93 (3H, d, J = 8.2 Hz), 7.83 (1H, dd, J = 8.8, 3.8 Hz), 7.65 (1H, d, J = 8.2 Hz), 7.53 (1H, td, J = 8.4, 2.9 Hz), 7.29-7.25 (2H, m), 7.19 (1H, s), 3.95 (3H, s ), 2.37 (3H, s)
5 ESI (LC-MS modo positivo) m/z 425 [(M+H)+]5 ESI (LC-MS positive mode) m / z 425 [(M + H) +]
Los compuestos de los números 1418 a 1427 enumerados en la Tabla 24, se sintetizaron como se describe en la Etapa 28.The compounds of numbers 1418 to 1427 listed in Table 24, were synthesized as described in Step 28.
Tabla 24Table 24
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1418 1418
- 6. áster metílico del ácido 6-piridin-2-il-1 -(tolueno-4-sulfonil) -1H- indol-2-carboxílico 407 6. 6-Pyridin-2-yl-1 - (toluene-4-sulfonyl) -1H- indole-2-carboxylic acid methyl ester 407
- 1419 1419
- p áster metílico del ácido 6-piridazin-3-il-1 -(tolueno-4-sulfonil)- 1 H-indol-2-carboxílico 408 6-pyridazin-3-yl-1 - (toluene-4-sulfonyl) - 1 H-indol-2-carboxylic acid methyl ester 408
- 1420 1420
- áster metílico del ácido 1-(tolueno-4-sulfonll)-6-(5- tr¡fluoromet¡l-p¡r¡din-2-ll)-1H-¡ndol-2-carboxílico 475 1- (Toluene-4-sulfonll) -6- (5- trfluoromet-1-p¡r¡din-2-ll) -1H-¡-dol-2-carboxylic acid methyl ester 475
- 1421 1421
- TI 1 áster metílico del ácido 1-(tolueno-4-sulfonil)-6-(6- tr¡fluoromet¡l-plrid¡n-2-il)-1H-¡ndol-2-carboxíl¡co 475 TI 1 1- (toluene-4-sulfonyl) -6- (6- trfluoromet-l-plrid¡n-2-yl) -1H-α-2-carboxylic acid methyl ester 475
- 1422 1422
- áster metílico del ácido 6-(5-cloro-plrid¡n-2-¡l)-1-(tolueno -4- sulfonll)-1H-indol-2-carboxíllco 441 6- (5-Chloro-plrid¡n-2-¡l) -1- (toluene -4-sulfonll) -1H-indole-2-carboxylic acid methyl ester 441
- 1423 1423
- áster metílico del ácido 1-(tolueno-4-sulfonil)-6-(3- trifluorometil-piridin-2-il)-1 H-indol-2-carboxílico 475 1- (Toluene-4-sulfonyl) -6- (3- trifluoromethyl-pyridin-2-yl) -1 H-indole-2-carboxylic acid methyl ester 475
- 1424 1424
- áster metílico del ácido 1-(tolueno-4-sulfonil)-6-(4- trifluorometil-piridin-2-il)-1 H-indol-2-carboxílico 475 1- (Toluene-4-sulfonyl) -6- (4- trifluoromethyl-pyridin-2-yl) -1 H-indole-2-carboxylic acid methyl ester 475
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1425 1425
- áster metílico del ácido 6-(3-cloro-piridin-2-il)-1-(tolueno -4- sulfonil)-1H-indol-2-carboxílico 441, 443 6- (3-Chloro-pyridin-2-yl) -1- (toluene -4-sulfonyl) -1H-indole-2-carboxylic acid methyl ester 441, 443
- 1426 1426
- ó áster metílico del ácido 6-(3-fluoro-piridin-2-il)-1-(tolueno -4- sulfonil)-1H-indol-2-carboxílico 425 or 6- (3-fluoro-pyridin-2-yl) -1- (toluene -4-sulfonyl) -1H-indole-2-carboxylic acid methyl ester 425
- 1427 1427
- o 0 ‘■"VsH áster metílico del ácido 6-(6-morfolin-4-il-piridazin-3-il) -1- (tolueno-4-sulfonll)-1H-indol-2-carboxílico 493 or 0 ‘■" VsH 6- (6-morpholin-4-yl-pyridazin-3-yl) -1- (toluene-4-sulfonll) -1H-indole-2-carboxylic acid methyl ester 493
Etapa 29: Síntesis de la [5-am¡no-1-(2-metil-1H-bencimidazol-5-¡l)-1H-p¡razol-4-il]-[5-(6-metoxi-pir¡d¡n-3-¡l)-1-(tolueno- 4-sulfon¡l)-1 H-índol-2-M] metanona (1428)Step 29: Synthesis of [5-amine-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [5- (6-methoxy-pyr D¡n-3-¡l) -1- (toluene-4-sulfon¡l) -1 H-indole-2-M] methanone (1428)
5 Una mezcla de dioxano (0.6 mi), [5-am¡no-1-(2-metil-1H-benc¡m¡dazol-5-¡l)-1H-p¡razol-4-¡l]-[5-bromo-1-(tolueno-4- sulfonll) -1H-lndol-2-ll]-metanona (60 mg, 0.102 mmol), diclorob¡s(trifenilfosfina)paladio (II) (14 mg, 0.020 mmol), ácido 2-metoxl-5-p¡rld¡na borónico (39 mg, 0.255 mmol), y una solución acuosa de bicarbonato de sodio 2 M (0.255 ml_, 0.51 mmol) se agitó a 140°C, durante seis minutos en un reactor de microondas. La mezcla de reacción se filtró a través de Celite, y se lavó con acetato de etilo y a continuación con metanol. El filtrado se secó sobre sulfato de 10 sodio anhidro. El desecante se eliminó por filtración y se llevó a cabo la concentración. El residuo obtenido se purificó por cromatografía de amino gel (diclorometano/metanol = 99/1 a 92/8). De este modo, se obtuvo la [5-amlno- 1 -(2-metll-1 H-bencimidazol-5-il)-1 H-pirazol-4-il]-[5-(6-metoxi-piridin-3-il)-1 -(tolueno-4-sulfonil)-1 H-¡ ndol-2-il]- metanona, como un sólido de color amarillo pálido (54 mg, 85%).5 A mixture of dioxane (0.6 mi), [5-am-1-1 (2-methyl-1H-benzamidazol-5-l) -1H-p.razole-4-l] - [5-Bromo-1- (toluene-4- sulfonll) -1H-lndol-2-ll] -methanone (60 mg, 0.102 mmol), dichlorob¡s (triphenylphosphine) palladium (II) (14 mg, 0.020 mmol) , boronic 2-methoxy-5-pldrna acid (39 mg, 0.255 mmol), and a 2M aqueous solution of sodium bicarbonate (0.255 ml_, 0.51 mmol) was stirred at 140 ° C, for six minutes at a microwave reactor. The reaction mixture was filtered through Celite, and washed with ethyl acetate and then with methanol. The filtrate was dried over anhydrous sodium sulfate. The desiccant was removed by filtration and the concentration was carried out. The obtained residue was purified by amino gel chromatography (dichloromethane / methanol = 99/1 to 92/8). In this way, [5-aml-1 - (2-metll-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [5- (6-methoxy-pyridin-3) was obtained -il) -1 - (toluene-4-sulfonyl) -1 H-ndol-2-yl] - methanone, as a pale yellow solid (54 mg, 85%).
1H-RMN (DMSO-De) 5: 12.50 (1H, s), 8.50 (1H, d, J = 2.4 Hz), 8.08-8.04 (4H, m), 7.94 (1H, d, J = 1.8 Hz), 7.77 (1H, 15 s), 7.74 (1H, dd, J = 9.1, 1.8 Hz), 7.63-7.61 (2H, m), 7.46-7.40 (2H, m), 7.30 (1H, dd, J = 8.5, 1.8 Hz), 7.25 (1H, s),1H-NMR (DMSO-De) 5: 12.50 (1H, s), 8.50 (1H, d, J = 2.4 Hz), 8.08-8.04 (4H, m), 7.94 (1H, d, J = 1.8 Hz), 7.77 (1H, 15 s), 7.74 (1H, dd, J = 9.1, 1.8 Hz), 7.63-7.61 (2H, m), 7.46-7.40 (2H, m), 7.30 (1H, dd, J = 8.5, 1.8 Hz), 7.25 (1H, s),
7.06 (2H, s), 6.93 (1H, d, J = 8.5 Hz), 3.90 (3H, s), 2.54 (3H, s), 2.37 (3H, s)7.06 (2H, s), 6.93 (1H, d, J = 8.5 Hz), 3.90 (3H, s), 2.54 (3H, s), 2.37 (3H, s)
ESI (LC-MS modo positivo) m/z 618 [(M+H)+]ESI (LC-MS positive mode) m / z 618 [(M + H) +]
Los compuestos de los números 1429 a 1462, y 1580 a 1590 enumerados en la Tabla 25, se sintetizaron como se describe en la Etapa 29.The compounds of Nos. 1429 to 1462, and 1580 to 1590 listed in Table 25, were synthesized as described in Step 29.
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1429 1429
- w- [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol -4-il]-[6- (6-morfolin-4-il-piridin-3 -il)-1-(tolueno-4-sulfonil)-1 H-indol-2-il] -metanona 673 w- [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol -4-yl] - [6- (6-morpholin-4-yl-pyridin-3 - il) -1- (toluene-4-sulfonyl) -1 H-indole-2-yl] -methanone 673
- 1430 1430
- [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol -4-il]-[6- piridin-3-il)-1-(tolueno -4-sulfonil)-1 H-indol-2-il] -metanona 588 [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol -4-yl] - [6- pyridin-3-yl) -1- (toluene -4-sulfonyl ) -1 H-indol-2-yl] -methanone 588
- 1431 1431
- Jj T*?_ [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol -4-il]-[5- (6-morfolin-4-il-piridin-3 -il)-1-(tolueno-4- sulfonil)-1 H-indol-2- il] -metanona 673 Jj T *? _ [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol -4-yl] - [5- (6-morpholin-4-yl-pyridin) -3 -il) -1- (toluene-4- sulfonyl) -1 H-indol-2- il] -methanone 673
- 1432 1432
- ¿ <^'cr [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol -4-il]-[5- piridin-3-il-1-(tolueno -4-sulfonil)-1 H-indol-2-il] -metanona 588 <^ 'Cr [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol -4-yl] - [5- pyridin-3-yl-1- (toluene -4-sulfonyl) -1 H-indole-2-yl] -methanone 588
- 1433 1433
- A 0xí^k^ [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol -4-il]-[5- (6-piperadin-1-il-piridin-3 -il)-1-(tolueno-4- sulfonil)-1 H-indol-2- il] -metanona 672 A 0xi ^ k ^ [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol -4-yl] - [5- (6-piperadin-1-yl-pyridin -3 -il) -1- (toluene-4-sulfonyl) -1 H-indol-2- il] -methanone 672
- 1434 1434
- [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol -4-il]-(5- (6-hidroxi-pi ridin-3-il)-1 -(tolueno-4-sulfonil)- 1 H-indol-2-il]- metanona 604 [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol -4-yl] - (5- (6-hydroxy-pi ridin-3-yl) -1 - (toluene-4-sulfonyl) - 1 H-indol-2-yl] - methanone 604
- 1435 1435
- \ Q [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol -4-il]-[6- (3,4,5,6-tetrahidro-2H [1,2']bipiridin-5'-il)- 1-(tolueno-4- sulfonil)-1 H-indol -2-il]-metanona 671 [Q-5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol -4-yl] - [6- (3,4,5,6-tetrahydro-2H [ 1,2 '] bipyridin-5'-yl) - 1- (toluene-4-sulfonyl) -1 H-indole -2-yl] -methanone 671
- 1436 1436
- [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol -4-il]-[6- (6-piperadin-1-il-piridin-3 -il)-1-(tolueno-4- sulfonil)-1H- indol- 2-il] -metanona 672 [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol -4-yl] - [6- (6-piperadin-1-yl-pyridin-3-yl) -1- (toluene-4-sulfonyl) -1H- indole- 2-yl] -methanone 672
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1437 1437
- h TV í ^ W O H—' [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol -4-il]-[6- [2-(4-metil-piperadin -1-il)-pi ridin-4-il]- 1-(tolueno -4-sulfonil)- 1 H-indol-2-il] -metanona 686 h TV í ^ WOH— '[5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol -4-yl] - [6- [2- (2- (4-methyl- piperadin -1-il) -pi ridin-4-il] - 1- (toluene -4-sulfonyl) - 1 H-indole-2-yl] -methanone 686
- 1438 1438
- b C rH W [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol -4-il]-[6- piridin-4-il-1-(tolueno -4-sulfonil)-1 H-indol-2-il] -metanona 588 b C rH W [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol -4-yl] - [6- pyridin-4-yl-1- (toluene - 4-sulfonyl) -1 H-indole-2-yl] -methanone 588
- 1439 1439
- <& [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol -4-il]-[6- (1-metil-1H-pirazol -4-il)-1 -(tolueno-4- sulfonil)-1 H-indol-2-il]- metanona 591 <& [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol -4-yl] - [6- (1-methyl-1H-pyrazole -4-yl) -1 - (toluene-4-sulfonyl) -1 H-indole-2-yl] - methanone 591
- 1440 1440
- x cS ■n ^ ÍNha w^V [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol -4-il]-[6- (5-metoxi-piridin-3-il) -1-(tolueno-4-sulfonil)- 1 H-indol -2-il]- metanona 618 x cS ■ n ^ ÍNha w ^ V [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol -4-yl] - [6- (5-methoxy-pyridin -3-il) -1- (toluene-4-sulfonyl) - 1 H-indole -2-yl] - methanone 618
- 1441 1441
- r |r VV [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol -4-il]-[6- (2-metoxi-piridin-3-il) -1-(tolueno-4-sulfonil)- 1 H-indol -2-il]- metanona 618 r | r VV [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H -pyrazol -4-yl] - [6- (2-methoxy-pyridin-3-yl) -1- (toluene-4-sulfonyl) - 1 H-indole -2-yl] - methanone 618
- 1442 1442
- frí=o ¿I v-c¿r [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol -4-il]-[6- (5-metanosulfonilo-piridin-3-il)-1-(tolueno-4- sulfonil)-1H- indol-2-il] -metanona 666 cold = o ¿I vc¿r [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol -4-yl] - [6- (5-methanesulfonyl-pyridin- 3-yl) -1- (toluene-4-sulfonyl) -1H- indole-2-yl] -methanone 666
- 1443 1443
- 6, $ [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol -4-il]-[6- (4-metil-pi ridin-2-il) -1-(tolueno-4-sulfonil)- 1 H-indol -2-il]- metanona 602 6, $ [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol -4-yl] - [6- (4-methyl-pi ridin-2-yl) -1- (toluene-4-sulfonyl) - 1 H-indole -2-yl] - methanone 602
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1444 1444
- 6 [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol -4-il]-[6- (4-morfolin-4-il-fenil)-1-(tolueno-4-sulfonil) -1 H-indol-2-il]- metanona 672 6 [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol -4-yl] - [6- (4-morpholin-4-yl-phenyl) -1- (toluene -4-sulfonyl) -1 H-indole-2-yl] - methanone 672
- 1445 1445
- h [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol -4-il]-[6- (2-metoxi-fenil)-1-(tolueno-4-sulfonil)-1H-indol -2-il]-metanona 617 h [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol -4-yl] - [6- (2-methoxy-phenyl) -1- (toluene-4-sulfonyl ) -1H-indole -2-yl] -methanone 617
- 1446 1446
- ó n ►*- H [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol -4-il]-[6- fenil-1 -(tolueno-4-sulfonil)-1 H-indol-2-il] -metanona 587 or n ► * - H [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol -4-yl] - [6- phenyl-1 - (toluene-4-sulfonyl) -1 H-indole-2-yl] -methanone 587
- 1447 1447
- 4 fyOfcp"- u -hYXr H [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol -4-il]-[5- (2-fluoro-fenil)-1-(tolueno-4-sulfonil)-1H-indol -2-il]-metanona 605 4 fyOfcp "- u -hYXr H [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol -4-yl] - [5- (2-fluoro-phenyl) -1 - (toluene-4-sulfonyl) -1H-indole -2-yl] -methanone 605
- 1448 1448
- é. H [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol -4-il]-[1- (tolueno-4-sulfonil)-5-(2-trifluorometil-fenil)- 1 H-indol-2-il]- metanona 655 and. H [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol -4-yl] - [1- (toluene-4-sulfonyl) -5- (2-trifluoromethyl-phenyl ) - 1 H-indole-2-yl] - methanone 655
- 1449 1449
- é U V'tQ-^V H [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol -4-il]-[5- (3-fluoro-fenil)-1-(tolueno-4-sulfonil)-1H-indol -2-il]-metanona 605 é U V'tQ- ^ VH [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol -4-yl] - [5- (3-fluoro-phenyl) -1 - (toluene-4-sulfonyl) -1H-indole -2-yl] -methanone 605
- 1450 1450
- i [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol -4-il]-[1- (tolueno-4-sulfonil)-5-(3-trifluorometil-fenil)- 1 H-indol-2-il]- metanona 655 i [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol -4-yl] - [1- (toluene-4-sulfonyl) -5- (3-trifluoromethyl-phenyl ) - 1 H-indole-2-yl] - methanone 655
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1451 1451
- 9-oh„ ‘«SCCr H [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol - 4-il]-[6-(2-fluoro-fenil)-1-(tolueno-4-sulfonil)-1 H-indol -2- il]-metanona 605 9-oh „'« SCCr H [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6- (2-fluoro-phenyl) -1- (toluene-4-sulfonyl) -1 H-indole -2-yl] -methanone 605
- 1452 1452
- n [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol - 4-il]-[6-(3-fluoro-fenil)-1-(tolueno-4-sulfonil)-1 H-indol -2- il]-metanona 605 n [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6- (3-fluoro-phenyl) -1- (toluene-4 -sulfonyl) -1 H-indole -2- yl] -methanone 605
- 1453 1453
- ó fT^i D'& ^xür N [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol - 4-il]-[6-(4-fluoro-fenil)-1-(tolueno-4-sulfonil)-1 H-indol -2- il]-metanona 605 or fT ^ i D '& ^ xür N [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazole-4-yl] - [6- (4-fluoro- phenyl) -1- (toluene-4-sulfonyl) -1 H-indole -2-yl] -methanone 605
- 1454 1454
- n ó ac*- [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol - 4-il]-[6-(2-cloro-fenil)-1-(tolueno-4-sulfonií)-1 H-indol -2- il]-metanona 621, 623 n or ac * - [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6- (2-chloro-phenyl) -1- (toluene-4-sulfonii) -1 H-indole -2-yl] -methanone 621, 623
- 1455 1455
- $ '-•‘■ai- [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol - 4-il]-[6-(3-clorofenil)-1-(tolueno-4-sulfonil)-1 H-indol -2- il]-metanona 621, 623 $ '- •' ■ ai- [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6- (3-chlorophenyl) -1 - (toluene-4-sulfonyl) -1 H-indole -2-yl] -methanone 621, 623
- 1456 1456
- ¿/ Xr ti [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol - 4-il]-[6-(4-cloro-fenil)-1-(tolueno-4-sulfonil)-1 H-indol- 2- il] -metanona 621, 623 ¿/ Xr ti [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol-4-yl] - [6- (4-chloro-phenyl) -1- ( toluene-4-sulfonyl) -1 H-indol- 2- yl] -methanone 621, 623
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1457 1457
- T T 1H .un. H [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol -4- il]-[1-(tolueno-4-sulfonil)-6-(2-trifluorometil-fenil)- 1H- indol-2-il] -metanona 655 T T 1H. A. H [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol -4-yl] - [1- (toluene-4-sulfonyl) -6- (2-trifluoromethyl -phenyl) - 1H- indole-2-yl] -methanone 655
- 1458 1458
- n & WVV [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol -4- il]-[1-(tolueno-4-sulfonil)-6-(3 -trifluorometilfenil)- 1H- indol-2-il]-metanona 655 n & WVV [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol -4-yl] - [1- (toluene-4-sulfonyl) -6- (3 -trifluoromethylphenyl) - 1H- indole-2-yl] -methanone 655
- 1459 1459
- * $ * tx XjLy_V_-tíH'- [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol -4- il]-[1 -(tol ueno-4-sulfonil) -6-(4-trifluorometilfenil)- 1H- indol-2-il]-metanona 655 * $ * tx XjLy_V_-tíH'- [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazole -4-yl] - [1 - (tol uene-4- sulfonyl) -6- (4-trifluoromethylphenyl) - 1 H- indole-2-yl] -methanone 655
- 1460 1460
- 4* 1>PÍ:V''Q-Í' [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol -4- il]-[1 -(tol ueno-4-sulfonil) -5-(4-trifluorometilfenil)- 1H- indol-2-il]-metanona 655 4 * 1> PI: V''Q-Í '[5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazole -4-yl] - [1 - (tol uene-4-sulfonyl) -5- (4-trifluoromethylphenyl) - 1 H- indole-2-yl] -methanone 655
- 1461 1461
- & H [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol -4- il]-[6-(2,4-difluoro-fenil)-1-(tolueno-4-sulfonil)-1H-indol- 2- il] -metanona 623 & H [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazol -4-yl] - [6- (2,4-difluoro-phenyl) -1- ( toluene-4-sulfonyl) -1H-indol- 2- il] -methanone 623
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1462 1462
- $ X'V*.r" ~ H [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 H-pirazol - 4-il]-[6-(3-cloro-4-fluorofenil)-1-(tolueno-4-sulfonil) -1H- indol-2-il]-metanona 640, 642 $ X'V * .r "~ H [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 H-pyrazole-4-yl] - [6- (3-chloro- 4-fluorophenyl) -1- (toluene-4-sulfonyl) -1H- indole-2-yl] -methanone 640, 642
- 1580 1580
- í ó o.rr VYíV [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4-il]-[6-(3-cloro-piridin-4-il)-1-(tolueno-4- sulfonil)-1H- indol-2-il]-metanona 622 í o o.rr VYíV [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4-yl] - [6- (3-chloro-pyridin-4-yl) -1- (toluene-4-sulfonyl) -1H- indole-2-yl] -methanone 622
- 1581 1581
- v, é y y ^--0 Vt0*- [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4-il]-[6-(6-metilpiridin-3-il)-1 -(tolueno-4- sulfonil)-1H- indol-2-il]-metanona 602 v, é yy ^ - 0 Vt0 * - [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpyrazol- 4-yl] - [6- (6-methylpyridin-3 -il) -1 - (toluene-4-sulfonyl) -1H- indole-2-yl] -methanone 602
- 1582 1582
- 1 .0 li) '¿* v^YXV "k~JJ [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol-4- il]-[6-(5-fluoro-piridin-3-il)-1-(tolueno-4- sulfonil)-1H- indol-2-il]-metanona 606 1 .0 li) '¿* v ^ YXV "k ~ JJ [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4- il] - [6- (5 -fluoro-pyridin-3-yl) -1- (toluene-4-sulfonyl) -1H- indole-2-yl] -methanone 606
- 1583 1583
- kl-or ^-vO? ‘■V [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4-il]-[1-(tolueno-4-sulfonil)-6-(2- trifluorometil-piridin-3- il)-1 H-indol-2-il]-metanona 656 kl-or ^ -vO? '■ V [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpyrazol-4-yl] - [1- (toluene-4-sulfonyl) -6- (2- trifluoromethyl -pyridin-3- il) -1 H-indol-2-yl] -methanone 656
- 1584 1584
- o- $ [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4-il]-[6-(5-cl o ro-2-metoxi-pi ridin-3-il)- 1-(tolueno-4- sulfonil)-1H-indol-2-il]-metanona 652 o- [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpyrazol-4-yl] - [6- (5-cl or ro-2-methoxy-pi ridin- 3-yl) - 1- (toluene-4-sulfonyl) -1H-indole-2-yl] -methanone 652
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1585 1585
- X £ WrV ^B [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4-il]-[6- (5-cloro-piridin-3-il)-1-(tolueno-4- sulfonil)-1 H-indol-2-il]- metanona 622 X £ WrV ^ B [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4-yl] - [6- (5-chloro-pyridin-3-yl) - 1- (toluene-4-sulfonyl) -1 H-indol-2-yl] - methanone 622
- 1586 1586
- [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4-il]-[6- tiofen-3-il-1-(tolueno-4-sulfonil)- 1H-indol-2-il]-metanona 593 [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4-yl] - [6- thiophene-3-yl-1- (toluene-4-sulfonyl) - 1H -indole-2-yl] -methanone 593
- 1587 1587
- v-ov [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4-il]-[6- (4-cloropiridin-3-il)-1-(tolueno-4- sulfonil)-1 H-indol-2-il]- metanona 622 v-ov [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4-yl] - [6- (4-chloropyridin-3-yl) -1- (toluene -4- sulfonyl) -1 H-indole-2-yl] - methanone 622
- 1588 1588
- [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4-il]-[6- thiphen-2-il-1 -(tol ueno-4-sulfonil)- 1H-indol-2-il]-metanona 593 [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4-yl] - [6- thiphen-2-yl-1 - (toluene-4-sulfonyl) - 1H-indole-2-yl] -methanone 593
- 1589 1589
- o0 ~rtxr [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4-il]-[6- (3-fluoro-pi ridin-4-il)-1-(tolueno-4- sulfonil)-1 H-indol-2-il]- metanona 606 o0 ~ rtxr [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpirazol- 4-yl] - [6- (3-fluoro-pi ridin-4-yl) -1 - (toluene-4-sulfonyl) -1 H-indol-2-yl] - methanone 606
- 1590 1590
- [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpirazol- 4-il]-[1- (tolueno-4-sulfonil)-6-(2- trifl uorometil-pi ridi n-4-il)-1 H-indol-2- il]-metanona 656 [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1-pyrazol-4-yl] - [1- (toluene-4-sulfonyl) -6- (2- trifl uoromethyl-pi ridi n -4-yl) -1 H-indol-2- yl] -methanone 656
Etapa 30: Síntesis de la [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-piridazin-4-il-1-(tolueno-4- sulfonil)- 1H-indol-2-il]-metanona (1463)Step 30: Synthesis of [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [6-pyridazin-4-yl-1- (toluene- 4- sulfonyl) - 1H-indole-2-yl] -methanone (1463)
Una mezcla de [5-am¡no-1-(2-met¡l-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-yodo-1-(tolueno-4-sulfon¡l)-1H-¡ndol-2-¡l]- metanona (194.9 mg, 0.306 mmol), aducto [1,1’-bis(difenilfosfino)ferroceno] dicloro-paladio (ll)/d¡clorometano (14.4 mg, 0.015 mmol) bis(pinacol)diborano (100.9 mg, 0.397 mmol), acetato de potasio (132.3 mg,1.35 mmol), y 5 dlmetllsulfóxldo (DMSO) anhidro (1.5 mi) se desaireó. A continuación, el aire se reemplazó tres veces con argón, y se calentó y se agitó a 110°C, durante seis horas. A continuación, la mezcla de reacción se extrajo con acetato de etilo. El extracto se secó sobre sulfato de sodio anhidro. El desecante se eliminó por filtración, y se llevó a cabo la concentración. A continuación, el residuo obtenido mediante concentración bajo presión reducida se sometió a cromatografía de columna de sílica gel (diclorometano/metanol = 15/1). El producto en bruto resultante se mezcló 10 con 4-bromo-piridazina (78.0 mg, 0.491 mol), diclorobis(trifenilfosfina)paladio (II) (17.2 mg, 0.025 mmol), una solución acuosa de bicarbonato de sodio 2 M (0.325 mmol), y dioxano (0.4 mi). Después de la desaireación, el aire se reemplazó tres veces con argón, y esta se sometió a microondas a 150°C, durante cinco minutos. A continuación, la mezcla de reacción se extrajo con acetato de etilo. El extracto se secó sobre sulfato de sodio anhidro. El desecante se eliminó por filtración, y se llevó a cabo la concentración. A continuación, el residuo obtenido mediante 15 concentración bajo presión reducida se purificó por cromatografía de columna de sílica gel (diclorometano/metanol = 1% a 12%). De este modo, se obtuvo [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[6-piridazin-4-il-1- (tolueno-4-sulfonil)-1H-indol-2-il]-metanona como un material amorfo de color amarillo pálido (20.0 mg, rendimiento del 11%).A mixture of [5-amine-1- (2-methyl-1H-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [6-iodo-1- (toluene-4-sulfon L) -1H-¡ndol-2-¡l] - methanone (194.9 mg, 0.306 mmol), adduct [1,1'-bis (diphenylphosphino) ferrocene] dichloro-palladium (ll) / dichloromethane (14.4 mg , 0.015 mmol) bis (pinacol) diborane (100.9 mg, 0.397 mmol), potassium acetate (132.3 mg, 1.35 mmol), and anhydrous 5-dimethyl sulfoxide (DMSO) deaerated. The air was then replaced three times with argon, and heated and stirred at 110 ° C, for six hours. Then, the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the concentration was carried out. Then, the residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography (dichloromethane / methanol = 15/1). The resulting crude product was mixed with 4-bromo-pyridazine (78.0 mg, 0.491 mol), dichlorobis (triphenylphosphine) palladium (II) (17.2 mg, 0.025 mmol), a 2M aqueous solution of sodium bicarbonate (0.325 mmol ), and dioxane (0.4 mi). After deaeration, the air was replaced three times with argon, and it was microwaved at 150 ° C for five minutes. Then, the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the concentration was carried out. Then, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (dichloromethane / methanol = 1% to 12%). Thus, [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1H-pyrazol-4-yl] - [6-pyridazin-4-yl-1- (toluene-] 4-sulfonyl) -1H-indole-2-yl] -methanone as a pale yellow amorphous material (20.0 mg, 11% yield).
ESI (LC-MS modo positivo) m/z 589 [(M+H)+]ESI (LC-MS positive mode) m / z 589 [(M + H) +]
20 Etapa 31: Síntesis de (1 -bencenosulfonil-1 H-indol-6-il) metanol (1464)Step 31: Synthesis of (1-benzenesulfonyl-1 H-indol-6-yl) methanol (1464)
Una cantidad predeterminada de hidruro de litio aluminio (167 mg, 4.42 mmol) se colocó en un recipiente de reacción, y tetrahidrofurano (THF) anhidro (15 mi) se le adicionó, y esta se enfrió a 0°C. Una solución en tetrahidrofurano (THF) anhidro (5 mi) de éster metílico del ácido 1-bencenosulfonil-1 H-indol-6-carboxílico (930 mg, 25 2.95 mmol) se adicionó a la mezcla. Esta se agitó a 0°C, durante 30 minutos. Una solución acuosa saturada conA predetermined amount of lithium aluminum hydride (167 mg, 4.42 mmol) was placed in a reaction vessel, and anhydrous tetrahydrofuran (THF) (15 ml) was added, and it was cooled to 0 ° C. A solution in anhydrous tetrahydrofuran (THF) (5 ml) of 1-benzenesulfonyl-1 H-indole-6-carboxylic acid methyl ester (930 mg, 2.95 mmol) was added to the mixture. This was stirred at 0 ° C for 30 minutes. An aqueous solution saturated with
cloruro de amonio (1 mi) se adicionó a la mezcla. Después de la filtración con celite, el Celite se lavó con diclorometano. El filtrado se secó sobre sulfato de sodio anhidro. El desecante se eliminó por filtración, y se llevó a cabo la concentración. A continuación, mediante concentración bajo presión reducida, se obtuvo el (1- bencenosulfonil-1H-indol-6-il)-metanol como un material de color marrón aceitosa (859 mg, 100%).Ammonium chloride (1 ml) was added to the mixture. After filtration with celite, the Celite was washed with dichloromethane. The filtrate was dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the concentration was carried out. Then, by concentration under reduced pressure, (1- benzenesulfonyl-1H-indole-6-yl) -methanol was obtained as an oily brown material (859 mg, 100%).
30 1H-RMN (DMSO-De) 8: 7.96-7.92 (3H, m), 7.74 (1H, d, J = 3.7 Hz), 7.68-7.67 (1H, m), 7.60-7.55 (2H, m), 7.52 (1H, d, J = 8.0 Hz), 7.19-7.17 (1H, m), 6.80 (1H, dd, J = 3.7, 0.8 Hz), 5.30 (1H, t, J = 5.7 Hz), 4.59 (2H, d, J = 5.7 Hz)30 1H-NMR (DMSO-De) 8: 7.96-7.92 (3H, m), 7.74 (1H, d, J = 3.7 Hz), 7.68-7.67 (1H, m), 7.60-7.55 (2H, m), 7.52 (1H, d, J = 8.0 Hz), 7.19-7.17 (1H, m), 6.80 (1H, dd, J = 3.7, 0.8 Hz), 5.30 (1H, t, J = 5.7 Hz), 4.59 (2H , d, J = 5.7 Hz)
ESI (LC-MS modo positivo) m/z 288 [(M+H)+]ESI (LC-MS positive mode) m / z 288 [(M + H) +]
Etapa 32: Síntesis del 1-bencenosulfonil-6-(fert-butil-difenil-silaniloximetil)-1H-indol (1465)Step 32: Synthesis of 1-benzenesulfonyl-6- (fert-butyl-diphenyl-silanyloxymethyl) -1H-indole (1465)
55
1010
15fifteen
20twenty
2525
PP
Cantidades predeterminadas de 1-bencenosulfonil-1H-indol-6-il)-metanol (859 mg, 2.99 mmol), ferí-butil difenil clorosilano (2.3 mi, 8.97 mmol), e imidazol (1.2 g, 17.9 mmol) se colocaron en un recipiente de reacción, y se le adicionó dimetilformamida (30 mi). Esta se agitó a temperatura ambiente, durante 20 horas. La mezcla de reacción se diluyó con acetato de etilo (60 mi). Esta se lavó dos veces con agua, y se secó sobre sulfato de sodio anhidro. El desecante se eliminó por filtración, y se llevó a cabo la concentración. El producto en bruto resultante se utilizó en reacciones posteriores.Default amounts of 1-benzenesulfonyl-1H-indole-6-yl) -methanol (859 mg, 2.99 mmol), fery-butyl diphenyl chlorosilane (2.3 mL, 8.97 mmol), and imidazole (1.2 g, 17.9 mmol) were placed in a reaction vessel, and dimethylformamide (30 ml) was added. This was stirred at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate (60 ml). This was washed twice with water, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the concentration was carried out. The resulting crude product was used in subsequent reactions.
Etapa 33: Síntesis del éster metílico del ácido 1 -bencenosulfonil-6-(íerí-butil-difenil-silaniloxi metil)-1 H-indol-2- carboxílico (1466)Step 33: Synthesis of the 1-benzenesulfonyl-6- (íeri-butyl-diphenyl-silanyloxymethyl) -1 H-indole-2-carboxylic acid methyl ester (1466)
Una solución en tetrahidrofurano (THF) de diisopropilamida de litio (LDA) se preparó adicionando una solución en hexano de n-butilo litio 1.0 M (2.8 mi, 4.49 mmol) gota a gota a una solución en tetrahidrofurano (THF) anhidro (5 mi) preenfriada (0°C) de N,N-diisopropil amina (0.64 mi, 4.49 mmol).A solution in lithium diisopropylamide tetrahydrofuran (THF) (LDA) was prepared by adding a solution in 1.0 M lithium n-butyl hexane (2.8 ml, 4.49 mmol) dropwise to a solution in anhydrous tetrahydrofuran (THF) ) precooled (0 ° C) of N, N-diisopropyl amine (0.64 ml, 4.49 mmol).
Una solución en tetrahidrofurano (THF) anhidro (20 mi) de 1-bencenosulfon¡l-6-(ferf-butll-d¡fenil-s¡lan¡lox¡met¡l)-1H- indol en bruto se enfrió a -78°C, y se le adicionó una solución preparada en tetrahidrofurano (THF) de diisopropilamida de litio (LDA). Esta se agitó a -78°C, durante 30 minutos. Se le adicionó cloroformlato de metilo (0.43 mi, 5.98 mmol), y esta se agitó a -78°C, durante 30 minutos. Se adicionó a la mezcla una solución acuosa saturada con cloruro de amonio de reacción, y esta se calentó a temperatura ambiente. Después de la extracción con acetato de etilo, la capa orgánica se secó sobre sulfato de sodio anhidro. El desecante se eliminó por filtración y se llevó a cabo la concentración. A continuación, el residuo obtenido mediante concentración bajo presión reducida se purificó por cromatografía de columna de síllca gel (hexano/acetato de etilo =98/2 to 4/1). Por lo tanto, se obtuvo éster metílico del ácido 1-bencenosulfonil-6-(fe/f-butil-difenil-silaniloximetil)-1H-indol-2-carboxílico como un material amorfo de color marrón (882 mg, 51%).A solution in anhydrous tetrahydrofuran (THF) (20 ml) of crude 1-benzenesulfon-6- (ferf-butll-d-phenyl-s¡lanxlomel) -1H-indole was cooled to - 78 ° C, and a solution prepared in lithium tetrahydrofuran (THF) of lithium diisopropylamide (LDA) was added. This was stirred at -78 ° C for 30 minutes. Methyl chloroformate (0.43 ml, 5.98 mmol) was added, and it was stirred at -78 ° C for 30 minutes. An aqueous solution saturated with reaction ammonium chloride was added to the mixture, and it was heated to room temperature. After extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate. The desiccant was removed by filtration and the concentration was carried out. Then, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate = 98/2 to 4/1). Therefore, 1-benzenesulfonyl-6- (fe / f-butyl-diphenyl-silyloxymethyl) -1H-indole-2-carboxylic acid methyl ester was obtained as a brown amorphous material (882 mg, 51%).
ESI (LC-MS modo positivo) m/z 584 [(M+H)+]ESI (LC-MS positive mode) m / z 584 [(M + H) +]
Etapa 34: Síntesis de éster etílico del ácido 5-(1-fert-butoxicarbonil-1,2,3,6-tetrahidro-piridin-4-il)-1-(tolueno-4- sulfonil)- 1H-lndol-2-carboxílico (1467)Step 34: Synthesis of 5- (1-fert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl) -1- (toluene-4-sulfonyl) - 1H-lndol-2 acid ester -carboxylic (1467)
OSOBEAR
nn
Éster etílico del ácido 5-bromo-1-(tolueno-4-sulfonil)- 1H-lndol-2-carboxílico (844 mg, 2.0 mmol), tert-butil áster del ácido 4-(4,4,5,5-tetramet¡l-[1,3,2]d¡oxaborolan-2-¡l)-3,6-d¡h¡dro-2H-pir¡d¡na-1-carboxílico (742 mg, 2.4 mmol), fosfato de potasio (848 mg, 4.0 mmol), y tetrakis(trifenilfosfina) paladio (116 mg, 0.1 mmol) se colocaron en un matraz. Después de la desaireación, el aire se reemplazó con nitrógeno. Se adicionaron dioxano anhidro (16 mi) y agua (4 5 mi) al matraz, y esta se agitó a 80°C, durante 15 horas. Después de enfriarla a temperatura ambiente, la mezcla de reacción se filtró a través de Celite, y a continuación se lavó con acetato de etilo. El filtrado se concentró, y el residuo obtenido mediante concentración bajo presión reducida se purificó por cromatografía de columna de sílica gel. De este modo, se obtuvo el éster etílico del ácido 5-(1-fert-butoxicarbon¡l-1,2,3,6-tetrahidro-piridin-4-il)-1-(tolueno-4- sulfonil)-1H-indol-2-carboxíl¡co como un material amorfo incoloro (1.0 g, 97.2%).5-Bromo-1- (toluene-4-sulfonyl) -1H-lndol-2-carboxylic acid ethyl ester (844 mg, 2.0 mmol), 4- (4,4,5,5-) acid tert-butyl ester tetramethyl- [1,3,2] dxaxaborolan-2-l) -3,6-d¡h¡dro-2H-pyrdine-1-carboxylic acid (742 mg, 2.4 mmol), Potassium phosphate (848 mg, 4.0 mmol), and tetrakis (triphenylphosphine) palladium (116 mg, 0.1 mmol) were placed in a flask. After deaeration, the air was replaced with nitrogen. Anhydrous dioxane (16 ml) and water (4.5 ml) were added to the flask, and it was stirred at 80 ° C for 15 hours. After cooling to room temperature, the reaction mixture was filtered through Celite, and then washed with ethyl acetate. The filtrate was concentrated, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography. In this way, 5- (1-fert-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl) -1- (toluene-4-sulfonyl) -1H ethyl ester was obtained -indole-2-carboxylic acid as a colorless amorphous material (1.0 g, 97.2%).
10 1H-RMN (DMSO-D6) 8: 7.96 (1H, d, J = 9.1 Hz), 7.84 (2H, d, J = 8.2 Hz), 7.68 (1H, d, J = 1.8 Hz), 7.60 (1H, dd, J =10 1H-NMR (DMSO-D6) 8: 7.96 (1H, d, J = 9.1 Hz), 7.84 (2H, d, J = 8.2 Hz), 7.68 (1H, d, J = 1.8 Hz), 7.60 (1H , dd, J =
9.1, 1.8 Hz), 7.41 (2H, d, J = 8.2 Hz), 7.34 (1H, s), 6.17 (1H, s), 4.34 (2H, q, J = 7.0 Hz), 4.02-3.98 (2H, m), 3.57-3.519.1, 1.8 Hz), 7.41 (2H, d, J = 8.2 Hz), 7.34 (1H, s), 6.17 (1H, s), 4.34 (2H, q, J = 7.0 Hz), 4.02-3.98 (2H, m), 3.57-3.51
(2H, m), 2.51-2.45 (1H, m), 2.34 (3H, s), 1.42 (9H, s), 1.32 (3H, t, J = 7.0 Hz)(2H, m), 2.51-2.45 (1H, m), 2.34 (3H, s), 1.42 (9H, s), 1.32 (3H, t, J = 7.0 Hz)
ESI (LC-MS modo positivo) m/z 525 [(M+H)+]ESI (LC-MS positive mode) m / z 525 [(M + H) +]
Los compuestos de los números 1468 y 1469 enumerados en la Tabla 26 se sintetizaron como se describe en la 15 Etapa 34.The compounds of Nos. 1468 and 1469 listed in Table 26 were synthesized as described in Step 34.
Tabla 26Table 26
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1468 1468
- o=s=o. JXXK-. ' c éster etílico del ácido 5-(1-tert-butoxicarbonil-1,2,3,6- tetrahidropiridin-4-il)-6-fl uoro-1 -(tolueno-4-sulfonil)-1 H- ¡ndol-2-carboxílico 543 o = s = o. JXXK-. 'c 5- (1-tert-Butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl) -6-fl uoro-1 - (toluene-4-sulfonyl) -1 H- ndol -2-carboxylic 543
- 1469 1469
- . f =: -T T ■r éster etílico del ácido 5-(1-tert-butoxicarbonil-1,2,3,6- tetrahidropiridin -4-¡l)-1 -(tol ueno-4-sulfoníl) -6- trifluorometil-1 H-Indol -2-carboxílico 593 . f =: -TT ■ r 5- (1-tert-Butoxycarbonyl-1,2,3,6-tetrahydropyridin-4-¡1) - - (toluene-4-sulfonyl) -6- trifluoromethyl acid -1 H-Indole -2-carboxylic 593
Etapa 35: Síntesis de 5-(1 -ferf-butoxicarbonil-piper¡din-4-¡l)-1 -(tolueno-4-sulfonil)-éster etílico del ácido 1 H-indol-2- carboxílico (1470)Stage 35: Synthesis of 5- (1-ferro-butoxycarbonyl-piperine-4-yl) -1 - (toluene-4-sulfonyl) -ethyl ester of 1 H-indole-2-carboxylic acid (1470)
Una mezcla de éster etílico del ácido 5-(1 -fe/t-butoxicarbonil-1,2,3,6-tetrahidro-piridin-4-il)-1 -(tolueno-4-sulfonil)-1 H- ¡ndol-2-carboxílico (495 mg, 0.9mmol), 5% paladio sobre carbono (100 mg), y metanol (20 mi) se agitó bajo unaA mixture of 5- (1 -fe / t-butoxycarbonyl-1,2,3,6-tetrahydro-pyridin-4-yl) -1 - (toluene-4-sulfonyl) -1 H- ndol acid ester -2-carboxylic (495 mg, 0.9mmol), 5% palladium on carbon (100 mg), and methanol (20 ml) was stirred under a
atmósfera de hidrógeno, durante 13 horas. La mezcla de reacción se filtró a través de Celite, y se lavó con acetato de etilo, y el filtrado se concentró. El residuo obtenido mediante concentración bajo presión reducida se purificó por cromatografía de columna de sílica gel. De este modo, se obtuvo el éster etílico del ácido 5-(1-ferí-butoxicarbonil- piperidin-4-il)-1 -(tolueno-4-sulfonil)- 1H-indol-2-carboxílico como un material amorfo incoloro (315.9 mg, 64%).hydrogen atmosphere, for 13 hours. The reaction mixture was filtered through Celite, and washed with ethyl acetate, and the filtrate was concentrated. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography. Thus, the 5- (1-feri-butoxycarbonyl-piperidin-4-yl) -1 - (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid ethyl ester was obtained as a colorless amorphous material ( 315.9 mg, 64%).
5 1H-RMN (DMSO-De) 8: 7.92 (1H, d, J = 8.8 Hz), 7.87 (2H, d, J = 7.9 Hz), 7.53 (1H, d, J = 1.5 Hz), 7.42 (2H, d, J = 7.9 Hz), 7.39 (1H, dd, J = 8.8, 1.5 Hz), 7.30 (1H, s), 4.33 (2H, q, J = 7.0 Hz), 4.12-4.00 (2H, m), 2.85-2.70 (3H, m), 2.35 (3H, s), 1.78-1.70 (2H, m), 1.54-1.44 (2H, m), 1.41 (9H, s), 1.31 (3H, t, J = 7.0 Hz)5 1H-NMR (DMSO-De) 8: 7.92 (1H, d, J = 8.8 Hz), 7.87 (2H, d, J = 7.9 Hz), 7.53 (1H, d, J = 1.5 Hz), 7.42 (2H , d, J = 7.9 Hz), 7.39 (1H, dd, J = 8.8, 1.5 Hz), 7.30 (1H, s), 4.33 (2H, q, J = 7.0 Hz), 4.12-4.00 (2H, m) , 2.85-2.70 (3H, m), 2.35 (3H, s), 1.78-1.70 (2H, m), 1.54-1.44 (2H, m), 1.41 (9H, s), 1.31 (3H, t, J = 7.0 Hz)
ESI (LC-MS modo positivo) m/z 527 [(M+H)+]ESI (LC-MS positive mode) m / z 527 [(M + H) +]
Los compuestos de los números 1471 y 1472 enumerados en la Tabla 27, se sintetizaron como se describe en la 10 Etapa 35.The compounds of Nos. 1471 and 1472 listed in Table 27, were synthesized as described in Step 35.
Tabla 27Table 27
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1471 1471
- $ 1 0 éster etílico del ácido 5-(1-tert-butoxicarbonll- piperidin-4-il)-6-fluoro-1 -(tolueno-4-sulfonil)-1 H- indol-2-carboxílico 489 [M- tert-Bu] 1-10 5- (1-tert-butoxycarbonll-piperidin-4-yl) -6-fluoro-1 - (toluene-4-sulfonyl) -1 H- indole-2-carboxylic acid ethyl ester 489 [M-tert -Bu]
- 1472 1472
- , ^ F ? OS‘Qr éster etílico del ácido 5-(1-tert-butox¡carbon¡l- p¡per¡din-4-il)-1-(tolueno-4-sulfon¡l)-6-tr¡fluoromet¡l - 1 H-indol-2-carboxílico 595 , ^ F? OS'Qr 5- (1-tert-butoxycarbonyl-p¡per¡din-4-yl) -1- (toluene-4-sulfonyl) -6-trifluoromethyl acid - 1 H-indole-2-carboxylic 595
Etapa 36: Síntesis del éster etílico del ácido 5-piperidin-4-il-1-(tolueno-4-sulfonil)- 1H-¡ndol-2-carboxílico (1473)Step 36: Synthesis of 5-piperidin-4-yl-1- (toluene-4-sulfonyl) - 1H-α-2-carboxylic acid ethyl ester (1473)
15 Se disolvió el éster etílico del ácido 5-(1-fert-Butoxicarbonil-piperidin-4-il)-1-(tolueno-4-sulfon¡l)- 1H-indol-2-carboxíl¡co (362 mg, 0.687 mmol) en una solución de la mezcla de acetato de etilo (4 mi) y ácido clorhídrico 4 M/acetato de etilo (8 mi). Esta se agitó a temperatura ambiente bajo una atmósfera de nitrógeno, durante 1.5 horas. La mezcla de reacción se concentró bajo presión reducida. De este modo, se obtuvo éster etílico del ácido 5-piper¡d¡n-4-¡l-1- (tolueno-4-sulfonil)- 1H-indol-2-carboxílico clorhidrato como un material amorfo incoloro (332 mg).The 5- (1-fert-Butoxycarbonyl-piperidin-4-yl) -1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid (362 mg, 0.687) mmol) in a solution of the mixture of ethyl acetate (4 ml) and 4M hydrochloric acid / ethyl acetate (8 ml). This was stirred at room temperature under a nitrogen atmosphere, for 1.5 hours. The reaction mixture was concentrated under reduced pressure. Thus, 5-piperine-4-yl-1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic hydrochloride ethyl ester was obtained as a colorless amorphous material (332 mg) .
1H-RMN (DMSO-Dg) 6: 8.78 (1H, brs), 7.98 (1H, d, J = 8.5 Hz), 7.90 (2H, d, J = 8.5 Hz), 7.51 (1H, s), 7.44 (2H, d, J = 8.5 Hz), 7.38-7.36 (2H, m), 4.34 (2H, q, J = 7.1 Hz), 3.02-2.90 (4H, m), 2.36 (3H, s), 1.95-1.78 (5H, m), 1.31 (3H, t, J = 7.1 Hz)1H-NMR (DMSO-Dg) 6: 8.78 (1H, brs), 7.98 (1H, d, J = 8.5 Hz), 7.90 (2H, d, J = 8.5 Hz), 7.51 (1H, s), 7.44 ( 2H, d, J = 8.5 Hz), 7.38-7.36 (2H, m), 4.34 (2H, q, J = 7.1 Hz), 3.02-2.90 (4H, m), 2.36 (3H, s), 1.95-1.78 (5H, m), 1.31 (3H, t, J = 7.1 Hz)
ESI (LC-MS modo positivo) m/z 427 [(M+H)+]ESI (LC-MS positive mode) m / z 427 [(M + H) +]
5 Los compuestos de los números 1474 y 1475 enumerados en la Tabla 28, se sintetizaron como se describe en la Etapa 36.The compounds of numbers 1474 and 1475 listed in Table 28, were synthesized as described in Step 36.
1010
Etapa 37: Síntesis del éster etílico del ácido de 5-(1 -isopropil-piperidin-4-il)-1 -(tolueno-4-sulfonil)- 1H-indol-2- carboxílico (1476)Step 37: Synthesis of 5- (1-Isopropyl-piperidin-4-yl) -1 - (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid ethyl ester (1476)
Una mezcla del éster etílico del ácido 5-piperidin-4-il-1 -(tolueno-4-sulfonil)- 1H-indol-2-carboxílico clorhidrato (253 mg, 0.592 mmol) en didoroetano (4 mi), trietilamina (0.17 mi, 1.18 mmol), acetona (1.44 mi, 19.6 mmol), ácido acético (0.28 mi, 4.89 mmol), y triacetoxiborohidruro de sodio (318 mg, 1.50 mmol) se agitó a temperatura ambiente,A mixture of the ethyl ester of 5-piperidin-4-yl-1 - (toluene-4-sulfonyl) -1H-indole-2-carboxylic hydrochloride (253 mg, 0.592 mmol) in didoroethane (4 ml), triethylamine (0.17 mi, 1.18 mmol), acetone (1.44 mi, 19.6 mmol), acetic acid (0.28 mi, 4.89 mmol), and sodium triacetoxyborohydride (318 mg, 1.50 mmol) was stirred at room temperature,
15 durante 14.5 horas. El pH de la mezcla de reacción se ajustó a 9 (básico) utilizando una solución acuosa saturada con bicarbonato de sodio. La mezcla se extrajo con acetato de etilo. El extracto se lavó con una solución acuosa saturada con cloruro de sodio, y a continuación se secó sobre sulfato de sodio anhidro. El desecante se eliminó por filtración, y se llevó a cabo la concentración. El residuo resultante se purificó por cromatografía de columna de amino gel (hexano/acetato de etilo = 92/8 a 35/65). De este modo,15 for 14.5 hours. The pH of the reaction mixture was adjusted to 9 (basic) using an aqueous solution saturated with sodium bicarbonate. The mixture was extracted with ethyl acetate. The extract was washed with an aqueous solution saturated with sodium chloride, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the concentration was carried out. The resulting residue was purified by amino gel column chromatography (hexane / ethyl acetate = 92/8 to 35/65). In this way,
20 se obtuvo el éster etílico del ácido 5-(1-¡sopropil-piperidin-4-il)-1 -(tolueno-4-sulfonil)- 1H-indol-2-carboxílico como un material como goma incoloro (191 mg, 69%).20 5- (1-Sopropyl-piperidin-4-yl) -1 - (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid ethyl ester was obtained as a colorless gum material (191 mg, 69%).
1H-RMN (DMSO-Da) 8: 7.91 (1H, d, J = 8.5 Hz), 7.87 (2H, d, J = 8.5 Hz), 7.52 (1H, d, J = 1.8 Hz), 7.42 (2H, d, J = 8.5 Hz), 7.39 (1H, dd, J = 9.2, 1.8 Hz), 7.31 (1H, s), 4.34 (2H, q, J = 7.1 Hz), 2.87 (2H, d, J = 11.6 Hz), 2.74-2.67 (1H, m), 2.56-2.53 (1H, m), 2.35 (3H, s), 2.21 (2H, dd, J = 11.6, 5.8 Hz), 1.77-1.74 (2H, m), 1.63-1.57 (2H, m), 1.31 (3H, t, J = 7.1 Hz), 0.98 (6H, d, J = 6.7 Hz)1H-NMR (DMSO-Da) 8: 7.91 (1H, d, J = 8.5 Hz), 7.87 (2H, d, J = 8.5 Hz), 7.52 (1H, d, J = 1.8 Hz), 7.42 (2H, d, J = 8.5 Hz), 7.39 (1H, dd, J = 9.2, 1.8 Hz), 7.31 (1H, s), 4.34 (2H, q, J = 7.1 Hz), 2.87 (2H, d, J = 11.6 Hz), 2.74-2.67 (1H, m), 2.56-2.53 (1H, m), 2.35 (3H, s), 2.21 (2H, dd, J = 11.6, 5.8 Hz), 1.77-1.74 (2H, m) , 1.63-1.57 (2H, m), 1.31 (3H, t, J = 7.1 Hz), 0.98 (6H, d, J = 6.7 Hz)
5 ESI (LC-MS modo positivo) m/z 469 [(M+H)+]5 ESI (LC-MS positive mode) m / z 469 [(M + H) +]
Los compuestos de los números 1477 a 1480 enumerados en la Tabla 29, se sintetizaron como se describe en la Etapa 37.The compounds of numbers 1477 to 1480 listed in Table 29, were synthesized as described in Step 37.
Tabla 29Table 29
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1477 1477
- Ó cM, yj éster etílico del ácido 6-fluoro-5-( 1-isopropil- piperidin-4-il)-1 -(tolueno-4-sulfonil)-1 H-indol-2- carboxílico 487 Ó cM, yj 6-fluoro-5- (1-isopropyl-piperidin-4-yl) -1 - (toluene-4-sulfonyl) -1 H-indole-2-carboxylic acid ethyl ester 487
- 1478 1478
- $ fTOHA a"J éster etílico del ácido 5-(1-ciclopentil-piperidin -4-il)- 1-(tolueno-4-sulfonil) -1H-indol-2-carboxílico 495 fTOHA to "J 5- (1-cyclopentyl-piperidin -4-yl) -1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid ethyl ester 495
- 1479 1479
- éster etílico del ácido 5-(1-ciclohexil-piperidin -4-il)- 1-(tolueno-4- sulfonil) -1H-indol-2-carboxílico 509 5- (1-Cyclohexyl-piperidin -4-yl) -1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid ethyl ester 509
- 1480 1480
- F Oti4 3' éster etílico del ácido 5-(1-isopropil-piperidin-4-il) -1- (tolueno-4-sulfonil)-6-trifluorometil-1H-indol-2- carboxílico 537 F Oti4 3 '5- (1-Isopropyl-piperidin-4-yl) -1- (toluene-4-sulfonyl) -6-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester 537
Etapa 38: Síntesis del 6-(1-metil-piper¡din-4-il)-1-(tolueno-4-sulfonil)-1H-¡ndol (1481)Stage 38: Synthesis of 6- (1-methyl-piperine-4-yl) -1- (toluene-4-sulfonyl) -1H-¡ndol (1481)
Preparación del reactivo de zinc:Preparation of zinc reagent:
Una solución en tetrahidrofurano (THF) anhidro (3.5 mi) de 4-cloro-1-metll-plperidina (8.56 mmol, 1.1 mi) se adicionó 5 a 80°C a una suspensión (0.5 mi) de magnesio (234 mg, 9.6 mmol) en tetrahidrofurano (THF) anhidro. Esta se agitó, durante una hora. Después de enfriarla a temperatura ambiente, la mezcla de reacción se adicionó gota a gota a una solución mixta de bromuro de zinc (1.1 g, 4.8 mmol) en tetrahidrofurano (THF) anhidro (2.0 mi) y anhidro 1-metil-2- pirrolidinona (0.6 mi). Esto se agitó, durante 30 minutos.A solution in anhydrous tetrahydrofuran (THF) (3.5 ml) of 4-chloro-1-metll-plperidine (8.56 mmol, 1.1 ml) was added 5 to 80 ° C to a suspension (0.5 ml) of magnesium (234 mg, 9.6 mmol) in anhydrous tetrahydrofuran (THF). It stirred for an hour. After cooling to room temperature, the reaction mixture was added dropwise to a mixed solution of zinc bromide (1.1 g, 4.8 mmol) in anhydrous tetrahydrofuran (THF) (2.0 mL) and anhydrous 1-methyl-2-pyrrolidinone (0.6 mi) This was stirred, for 30 minutes.
Reacción de acoplamiento:Coupling reaction:
10 6-Bromo-1-(tolueno-4-sulfonll)-1H-¡ndol (340 mg, 0.97 mmol), Trls(dibencil¡denoacetona)d¡paladio (0) (23 mg, 0.025 mmol), y (3-dietoxifosfinotloylsulfanil-1,4-dioxan-2-il)sulfanll-d¡etoxi-sulfanil¡deno-fosforano (Ruphos) (47 mg, 0.1 mmol) se colocaron en un recipiente de reacción. Después de la desaireación, el aire se reemplazó con nitrógeno. Se le adicionaron tetrahidrofurano (THF) anhidro (5.0 mi) y una suspensión de reactivo de zinc preparado, y esta se agitó a 70°C, durante 17 horas. Después de enfriarla a temperatura ambiente, la mezcla de reacción se alcalinizó 15 con una solución acuosa saturada con bicarbonato de sodio. El sólido precipitado se eliminó por filtración. El filtrado se extrajo con acetato de etilo. El extracto se lavó con agua y una solución acuosa saturada con cloruro de sodio, y se secó sobre sulfato de sodio anhidro. El desecante se eliminó por filtración y se llevó a cabo la concentración. El residuo obtenido mediante concentración bajo presión reducida se purificó por cromatografía de columna de sílica gel. De este modo, se obtuvo 6-(1 -metil-piperidin-4-il)-1 -(tolueno-4-sulfonil)-1 H-indol como un sólido como cera 20 (293.7 mg, 82%).10 6-Bromo-1- (toluene-4-sulfonll) -1 H -indole (340 mg, 0.97 mmol), Trls (dibenzyldenoacetone) d palladium (0) (23 mg, 0.025 mmol), and (3 -diethoxyphosphinothloylsulfanyl-1,4-dioxan-2-yl) sulfanll-d-ethoxy-sulfanyldeno-phosphorane (Ruphos) (47 mg, 0.1 mmol) was placed in a reaction vessel. After deaeration, the air was replaced with nitrogen. Anhydrous tetrahydrofuran (THF) (5.0 ml) and a suspension of prepared zinc reagent were added, and this was stirred at 70 ° C for 17 hours. After cooling to room temperature, the reaction mixture was made alkaline with an aqueous solution saturated with sodium bicarbonate. The precipitated solid was removed by filtration. The filtrate was extracted with ethyl acetate. The extract was washed with water and an aqueous solution saturated with sodium chloride, and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and the concentration was carried out. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography. Thus, 6- (1-methyl-piperidin-4-yl) -1 - (toluene-4-sulfonyl) -1 H-indole was obtained as a solid as wax 20 (293.7 mg, 82%).
1H-RMN (DMSO-De) 8: 7.83 (2H, d, J = 8.2 Hz), 7.75 (1H, d, J = 1.5 Hz), 7.71 (1H, d, J = 3.7 Hz), 7.48 (1H, d,J = 8.1Hz), 7.38 (2H, d, J = 8.2 Hz), 7.14 (1H, dd, J = 8.1, 1.5 Hz), 6.76 (1H, d, J = 3.7 Hz), 2.89-2.87 (2H, m), 2.61-2.52 (1H, m), 2.31 (3H, s), 2.21 (3H, s), 1.99 (2H, td, J = 11.4, 5.7 Hz), 1.76-1.62 (4H, m)1H-NMR (DMSO-De) 8: 7.83 (2H, d, J = 8.2 Hz), 7.75 (1H, d, J = 1.5 Hz), 7.71 (1H, d, J = 3.7 Hz), 7.48 (1H, d, J = 8.1Hz), 7.38 (2H, d, J = 8.2 Hz), 7.14 (1H, dd, J = 8.1, 1.5 Hz), 6.76 (1H, d, J = 3.7 Hz), 2.89-2.87 ( 2H, m), 2.61-2.52 (1H, m), 2.31 (3H, s), 2.21 (3H, s), 1.99 (2H, td, J = 11.4, 5.7 Hz), 1.76-1.62 (4H, m)
ESI (LC-MS modo positivo) m/z 369 [(M+H)+]ESI (LC-MS positive mode) m / z 369 [(M + H) +]
25 Los compuestos de los números 1482 y 1483 enumerados en la Tabla 30, se sintetizaron como se describe en la Etapa 38.The compounds of Nos. 1482 and 1483 listed in Table 30, were synthesized as described in Step 38.
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1482 1482
- o-s-o éster etílico del ácido 6-fluoro-5-(1 -metil-piperidin-4-¡l)-1 - (tolueno -4- sulfonil)-1 H-indol-2-carboxílico 459 o-s-o 6-fluoro-5- (1-methyl-piperidin-4-1) ethyl ester -1 - (toluene -4-sulfonyl) -1 H-indole-2-carboxylic acid 459
- 1483 1483
- (J. O'5-O éster etílico del ácido 5-(1 -metil-piperidin-4-il) -1-(tolueno- 4-sulfonil)-1 H-indol-2-carboxílico 441 (J. O'5-O 5- (1-methyl-piperidin-4-yl) -1- (toluene-4-sulfonyl) -1 H-indole-2-carboxylic acid ethyl ester 441
Etapa 40: Síntesis del áster metílico del ácido 4-cloro-1-(tolueno-4-sulfonil)-1H-indol-2-carboxílico (1484)Step 40: Synthesis of 4-chloro-1- (toluene-4-sulfonyl) -1H-indole-2-carboxylic acid methyl ester (1484)
ClCl
5 Una solución de diisopropilamida de litio se preparó adicionando, a -78°C, una solución en hexano de n-butllo litio 1.0 M a una solución en tetrahidrofurano (THF) anhidro (1.5 mi) de dlisopropil amina (370 mi). La solución preparada se adicionó a -78°C a una solución en tetrahidrofurano (THF) (6 mi) de 4-cloro-1-(tolueno-4-sulfonil)-1H-¡ndol. Esto se agitó, durante 15 minutos. Después de adicionar cloroformlato de metilo (169 pl) a esta, la mezcla de reacción se agitó a -78°C, durante 15 minutos, y a continuación una solución acuosa (4 mi) de ácido clorhídrico 1 M se le 10 adicionó a -78°C. Después de calentarla a temperatura ambiente, la mezcla de reacción se extrajo con acetato de etilo (10 mi). La capa orgánica se lavó con una solución acuosa saturada con cloruro de sodio, y la capa orgánica se concentró bajo presión reducida. El residuo resultante se purificó por cromatografía de columna de sílica gel (hexano/acetato de etilo). De este modo, se obtuvo el éster metílico del ácido 4-cloro-1-(tolueno-4-sulfonil)-1H-¡ndol- 2-carboxílico como un sólido Incoloro (591 mg, 82%).5 A solution of lithium diisopropylamide was prepared by adding, at -78 ° C, a solution in hexane of 1.0 M lithium n-butyl to a solution in anhydrous tetrahydrofuran (THF) (1.5 ml) of dlisopropyl amine (370 ml). The prepared solution was added at -78 ° C to a solution in tetrahydrofuran (THF) (6 ml) of 4-chloro-1- (toluene-4-sulfonyl) -1 H -indole. This was stirred, for 15 minutes. After adding methyl chloroformate (169 pl) to it, the reaction mixture was stirred at -78 ° C, for 15 minutes, and then an aqueous solution (4 ml) of 1 M hydrochloric acid was added to -78 ° C. After heating to room temperature, the reaction mixture was extracted with ethyl acetate (10 ml). The organic layer was washed with an aqueous solution saturated with sodium chloride, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate). Thus, the 4-chloro-1- (toluene-4-sulfonyl) -1H-yndol-2-carboxylic acid methyl ester was obtained as a colorless solid (591 mg, 82%).
ESI (LC-MS modo positivo) m/z 364, 366 [(M+H)+]ESI (LC-MS positive mode) m / z 364, 366 [(M + H) +]
Los compuestos de los números 1485 a 1490 enumerados en la Tabla 31, se sintetizaron como se describe en la Etapa 39.The compounds of numbers 1485 to 1490 listed in Table 31, were synthesized as described in Step 39.
Tabla 31Table 31
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1485 1485
- CCfi éster metílico del ácido 3-fluoro-1-(tolueno-4- sulfonil) -1 H-lndol-2-carboxílico 348 CCfi 3-fluoro-1- (toluene-4-sulfonyl) -1 H-lndol-2-carboxylic acid methyl ester 348
- 1486 1486
- £ éster metílico del ácido 6-(1-metil-piperidln-4-¡l)-1 - (tolueno-4-sulfonil)-1 H-Indol -2-carboxíllco 427 £ 6- (1-Methyl-piperidln-4-¡1) -1 - (toluene-4-sulfonyl) -1 H-Indole -2-carboxylic acid methyl ester 427
- 1487 1487
- éster etílico del ácido 1-bencenosulfonil-5-fluoro-6- morfolin-4-ilmetil-1H-lndol-2-carboxíllco 447 1-Benzenesulfonyl-5-fluoro-6- morpholin-4-ylmethyl-1H-lndol-2-carboxylic acid ethyl ester 447
- 1488 1488
- 9 éster etílico del ácido 1-bencenosulfonll-5-(4-tert- butoxicarbonilpiperadin-1-¡lmetll)-1H-lndol-2- carboxílico 528 9 1-benzenesulfonll-5- (4-tert-butoxycarbonylpiperadin-1-lmetll) -1H-lndol-2-carboxylic acid ethyl ester 528
- 1489 1489
- * XXH- éster metílico del ácido 1-bencenosulfoníl-6-(tert- butil -difenilsilaniloximetil) -1H-¡ndol-2-carboxíl¡co 584 * XXH- 1-benzenesulfonyl-6- (tert-butyl-diphenylsilanyloxymethyl) -1H-α-2-carboxylic acid methyl ester 584
- 1490 1490
- P si 1 *XjCcH^ éster etílico del ácido 1-bencenosulfoníl-5-(4-tert- butoxicarbonil piperadin-1 -ilmetil)-1 H-indol-2- carboxílico 528 P si 1 * XjCcH ^ 1-benzenesulfonyl-5- (4-tert-butoxycarbonyl piperadin-1-methylmethyl) -1 H-indole-2-carboxylic acid ethyl ester 528
Etapa 40: Síntesis de (2-met¡l-1H-benc¡m¡dazol-5-il)-hidraz¡na diclorhidrato (1491)Stage 40: Synthesis of (2-methyl-1H-benzyldazol-5-yl) -hydrazine dihydrochloride (1491)
Se disolvió 5-amino-2-metil-1H-bencimidazol clorhidrato (16.51 g) en ácido clorhídrico concentrado (200 mi), y esta se enfrió a 0°C. Una solución acuosa (15 mi) de nitrito de sodio (7.59 g) se le adicionó gota a gota a 0°C, durante 20 minutos. Esta se agitó, durante 20 minutos. A continuación, una solución de ácido clorhídrico concentrado (20 mi) de 5 cloruro de estaño (II) dihidrato (55.7 g) se adicionó gota a gota a esta a 0°C, durante una hora, y a continuación esta se agitó, durante 30 minutos.5-Amino-2-methyl-1 H -benzimidazole hydrochloride (16.51 g) was dissolved in concentrated hydrochloric acid (200 ml), and it was cooled to 0 ° C. An aqueous solution (15 ml) of sodium nitrite (7.59 g) was added dropwise at 0 ° C, for 20 minutes. This was stirred for 20 minutes. Then, a solution of concentrated hydrochloric acid (20 ml) of 5-tin (II) chloride dihydrate (55.7 g) was added dropwise thereto at 0 ° C, for one hour, and then it was stirred, for 30 minutes
El sólido precipitado se recolectó por filtración, y se lavó con agua, y se secó. De este modo, se obtuvo la (2-metil- 1 H-bencimidazol-5-il)-hidrazina diclorhidrato en bruto.The precipitated solid was collected by filtration, and washed with water, and dried. Thus, the crude (2-methyl-1 H-benzimidazol-5-yl) -hydrazine dihydrochloride was obtained.
ESI (LC-MS modo positivo) m/z 163 [(M+H)+]ESI (LC-MS positive mode) m / z 163 [(M + H) +]
10 Los compuestos de los números 1492 a 1496 enumerados en la Tabla 32, se sintetizaron como se describe en la Etapa 40.The compounds of numbers 1492 to 1496 listed in Table 32, were synthesized as described in Step 40.
Tabla 32Table 32
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1492 1492
- h (2-et¡l-1 H-bencimidazol-5-il)-hidrazina diclorhidrato 177 h (2-et¡l-1 H-benzimidazol-5-yl) -hydrazine dihydrochloride 177
- 1493 1493
- (2-isopropil-1H-bencimidazol -5-il)-hidrazina diclorhidrato 191 (2-Isopropyl-1H-benzimidazol -5-yl) -hydrazine dihydrochloride 191
- 1494 1494
- (2-propil-1 H-bencimidazol-5-il)-hidrazina diclorhidrato 191 (2-propyl-1 H-benzimidazol-5-yl) -hydrazine dihydrochloride 191
- 1495 1495
- ti 9 (2-trifluorometil-1H-bencimidazol-5-il)-hidrazina diclorhidrato 217 ti 9 (2-trifluoromethyl-1H-benzimidazol-5-yl) -hydrazine dihydrochloride 217
- 1496 1496
- (2-bencil-1H -bencimidazol-5-il)-hidrazina diclorhidrato 239 (2-Benzyl-1 H -benzimidazol-5-yl) -hydrazine dihydrochloride 239
Etapa 41: Síntesis de (7-fluoro-2-met¡i iuStage 41: Synthesis of (7-fluoro-2-met¡i iu
' ll'’-benc¡m¡dazol-5-il)-h¡draz¡na diclorhidrato (1497)'ll' - benc¡m¡dazol-5-il) -h¡draz¡na dihydrochloride (1497)
55
1010
15fifteen
20twenty
2525
3030
Se preparó un catalizador de la siguiente manera. Se disolvieron acetato de paladio (1.2 mg, 0.0052 mmol) y 2- diciclohexil fosfino-2’,4’,6’-tri-i-propil-1,1’-bifenil (X-PHOS) (4.2 mg, 0.0088 mmol) en alcohol fe/f-amílico (2.4 jxl, 0.022 mmol) y N-metlI-morfolina (0.05 mi). La solución resultante se calentó y se agitó a 60°C bajo una atmósfera de nitrógeno, durante cinco minutos.A catalyst was prepared as follows. Palladium acetate (1.2 mg, 0.0052 mmol) and 2- dicyclohexyl phosphino-2 ', 4', 6'-tri-i-propyl-1,1'-biphenyl (X-PHOS) (4.2 mg, 0.0088 mmol) were dissolved ) in fe / f-amyl alcohol (2.4 jxl, 0.022 mmol) and N-methyl-morpholine (0.05 ml). The resulting solution was heated and stirred at 60 ° C under a nitrogen atmosphere, for five minutes.
En un recipiente de reacción separado, 7-fluoro-2-metil-3H-bencimidazol-5-il amina (100 mg, 0.44 mmol), litio bis(trimetilsilil) amida (190 mg, 1.1 mmol), y benzofenona hidrazona (94.3 mg, 0.48 mmol) se disolvieron en N-metil- morfolina (0.5 mi) bajo una atmósfera de nitrógeno. A continuación, se le adicionó la solución preparada que contiene el catalizador. Después de la desaireación, esta se calentó y se agitó a 100°C bajo una atmósfera de nitrógeno, durante dos horas. La mezcla de reacción se enfrió a temperatura ambiente, y a continuación una solución acuosa de ácido clorhídrico 6 M (0.5 mi) se le adicionó. La capa orgánica se aisló, y se concentró bajo presión reducida. De este modo, se obtuvo la N-benzhidrilideno-N’-(7-fluoro-2-metil-1H-bencimidazol-5-il)-hidrazina en bruto. El producto en bruto obtenido se utilizó en reacciones posteriores sin ser purificado.In a separate reaction vessel, 7-fluoro-2-methyl-3H-benzimidazol-5-yl amine (100 mg, 0.44 mmol), lithium bis (trimethylsilyl) amide (190 mg, 1.1 mmol), and benzophenone hydrazone (94.3 mg, 0.48 mmol) were dissolved in N-methyl morpholine (0.5 ml) under a nitrogen atmosphere. Then, the prepared solution containing the catalyst was added. After deaeration, it was heated and stirred at 100 ° C under a nitrogen atmosphere for two hours. The reaction mixture was cooled to room temperature, and then a 6 M aqueous hydrochloric acid solution (0.5 ml) was added. The organic layer was isolated, and concentrated under reduced pressure. Thus, the crude N-benzhydrylidene-N '- (7-fluoro-2-methyl-1H-benzimidazol-5-yl) -hydrazine was obtained. The crude product obtained was used in subsequent reactions without being purified.
Se adicionó ácido clorhídrico concentrado (0.7 mi) a una mezcla de la N-benzhidrilideno-N’-(7-fluoro- 2-metil-1H- bencimidazol-5-il)-hidrazina (325 mg) en bruto y etanol (0.7 mi). Esta se agitó a 59 a 64°C, durante una hora, y la mezcla de reacción se enfrió a temperatura ambiente. A continuación, el sólido precipitado se recolectó por filtración y se secó. De este modo, se obtuvo la 7-fluoro-2-metil-1H-bencimidazol-5-il-hidrazina diclorhidrato (90 mg, 80%).Concentrated hydrochloric acid (0.7 ml) was added to a mixture of the crude N-benzhydrylidene-N '- (7-fluoro-2-methyl-1 H- benzimidazol-5-yl) -hydrazine (325 mg) and ethanol (0.7 me). This was stirred at 59 at 64 ° C, for one hour, and the reaction mixture was cooled to room temperature. Then, the precipitated solid was collected by filtration and dried. Thus, 7-fluoro-2-methyl-1 H -benzimidazol-5-yl hydrazine dihydrochloride (90 mg, 80%) was obtained.
1H-RMN (DMSO-De) 8: 7.11 (1.0H, d, J = 1.8 Hz), 6.99 (1.0H, dd, J = 12.4, 1.8 Hz), 2.69 (3.1H, s)1H-NMR (DMSO-De) 8: 7.11 (1.0H, d, J = 1.8 Hz), 6.99 (1.0H, dd, J = 12.4, 1.8 Hz), 2.69 (3.1H, s)
ESI (LC-MS modo positivo) m/z 181 [(M+H)+jESI (LC-MS positive mode) m / z 181 [(M + H) + j
6-Fluoro-2-metil-1H-bencimidazol-5-il-hidrazina diclorhidrato (1498), se sintetizó como se describe en la Etapa 41.6-Fluoro-2-methyl-1H-benzimidazol-5-yl-hydrazine dihydrochloride (1498), was synthesized as described in Step 41.
4-Bromofenileno diamina (935 mg, 5.0 mmol) y ácido difluoroacético (0.47 mi, 7.5 mmol, 1.5 eq.) se disolvieron en una solución acuosa (10 mi) de ácido clorhídrico 5 M. Esto se agitó a 100°C, durante 24 horas. Después de enfriarla a temperatura ambiente, la mezcla de reacción se alcalinizó adicionando una solución acuosa (10 mi) de hidróxido de sodio 5 M a esta. Después de la extracción con acetato de etilo, el extracto se secó sobre sulfato de sodio anhidro. El desecante se eliminó por filtración y se llevó a cabo la concentración. El residuo obtenido mediante concentración bajo presión reducida se purificó por cromatografía de columna de sílica gel. De este modo, se obtuvo la 6-bromo-2-d¡fluoro-metil-1H-benc¡m¡dazol como un sólido de color amarillo pálido (1.0 g, 85.4%).4-Bromophenylene diamine (935 mg, 5.0 mmol) and difluoroacetic acid (0.47 ml, 7.5 mmol, 1.5 eq.) Were dissolved in an aqueous solution (10 ml) of 5 M hydrochloric acid. This was stirred at 100 ° C for 24 hours. After cooling to room temperature, the reaction mixture was made alkaline by adding an aqueous solution (10 ml) of 5 M sodium hydroxide to it. After extraction with ethyl acetate, the extract was dried over anhydrous sodium sulfate. The desiccant was removed by filtration and the concentration was carried out. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography. In this way, 6-bromo-2-d-fluoro-methyl-1H-benzyldazole was obtained as a pale yellow solid (1.0 g, 85.4%).
FF
ESI (LC-MS modo positivo) m/z 181[(M+H)+]ESI (LC-MS positive mode) m / z 181 [(M + H) +]
Etapa 42: Síntesis de 6-bromo-2-difluoromet¡l-1H-bencimidazol (1499)Stage 42: Synthesis of 6-bromo-2-difluoromet-1-1-benzimidazole (1499)
HH
1H-RMN (DMSO-De) 8: 13.51 (1H, brs), 7.86 (1H, d, J = 1.8 Hz), 7.62 (1H, d, J = 8.5 Hz), 7.44 (1H, dd, J = 8.5, 1.8 Hz), 7.41-7.14 (1H, m)1H-NMR (DMSO-De) 8: 13.51 (1H, brs), 7.86 (1H, d, J = 1.8 Hz), 7.62 (1H, d, J = 8.5 Hz), 7.44 (1H, dd, J = 8.5 , 1.8 Hz), 7.41-7.14 (1H, m)
ESI (LC-MS modo positivo) m/z 247, 249 [(M+H)+]ESI (LC-MS positive mode) m / z 247, 249 [(M + H) +]
Etapa 43: Síntesis de 6-bromo-2-difluorometil-1-(2-trimetilsilanil-etoximetil)-1H-bencimidazol (1500)Step 43: Synthesis of 6-bromo-2-difluoromethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole (1500)
\ / Si-\ / Yes-
55
Se adicionó (2-cloro-metoxi-etil)-trimetil-silano (1.1 mi, 6.4 mmol, 1.5 eq.) a una solución en diclorometano anhidro (22 mi) de 6-bromo-2-difluorometil-1H-bencimidazol (1.0 g, 4.27 mmol) y N,N-diisopropil etil amina (1.9 mi, 10.6 mmol, 2.5 eq.). Esto se agitó a temperatura ambiente, durante 18 horas. La mezcla de reacción se concentró. El residuo obtenido mediante concentración bajo presión reducida se purificó por cromatografía de columna de sílica 10 gel. De este modo, se obtuvo el 6-bromo-2-difluorometil-1-(2-trimetilsilanil-etoximetil)-1H-bencimidazol como un sólido de color amarillo (1.37 g, 85%).(2-Chloro-methoxy-ethyl) -trimethyl-silane (1.1 ml, 6.4 mmol, 1.5 eq.) Was added to a solution in anhydrous dichloromethane (22 ml) of 6-bromo-2-difluoromethyl-1 H -benzimidazole (1.0 g, 4.27 mmol) and N, N-diisopropyl ethyl amine (1.9 ml, 10.6 mmol, 2.5 eq.). This was stirred at room temperature for 18 hours. The reaction mixture was concentrated. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography. Thus, 6-bromo-2-difluoromethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzimidazole was obtained as a yellow solid (1.37 g, 85%).
1H-RMN (DMSO-De) 8: 8.07-8.02 (1H, m), 7.78-7.74 (1H, m), 7.60-7.28 (2H, m), 5.76 (2H, s), 3.52 (2H, td, J = 8.4,1H-NMR (DMSO-De) 8: 8.07-8.02 (1H, m), 7.78-7.74 (1H, m), 7.60-7.28 (2H, m), 5.76 (2H, s), 3.52 (2H, td, J = 8.4,
2.6 Hz), 0.83 (2H, td, J = 8.4, 2.6 Hz), -0.10 (9H, s)2.6 Hz), 0.83 (2H, td, J = 8.4, 2.6 Hz), -0.10 (9H, s)
ESI (LC-MS modo positivo) m/z 377, 379 [(M+H)+]ESI (LC-MS positive mode) m / z 377, 379 [(M + H) +]
15 Etapa 44: Sintesis de 2-difluorometil-3-(2-trimetilsilanil-etox¡met¡l)-3H-bencim¡dazol-5-¡l]-h¡draz¡na clorhidrato (1501)15 Stage 44: Synthesis of 2-difluoromethyl-3- (2-trimethylsilanyl-ethoxymethyl) -3H-benzimdadazol-5-l] -hrazine hydrochloride (1501)
\ /\ /
Si-Yes-
HCIHCI
6-Bromo-2-difluorometil-1-(2-trimetils¡lanil-etoximetil)-1H-bencimidazol (754 mg, 2.0 mmol), Tris(dibencilidenoacetona)dipaladio (0) (92 mg, 0.1 mmol), 2-diciclohexilfosfino-2’,4’,6’-tri-i-propil-1,1’-bifenil (X- PHOS) (143 mg, 0.3 mmol), carbonato de ceslo (1.3 g, 4.0 mmol), y tert-butil carbazato (794 mg, 6.0 mmol) se 20 colocaron en un matraz. Después de la desalreaclón, el aire se reemplazó con argón. Se le adicionó tolueno anhidro (8.0 mi), y esta se agitó a 100°C, durante 20 horas. Después de enfriarla a temperatura ambiente, la mezcla de reacción se filtró a través de Celite, y se lavó con acetato de etilo. El filtrado se concentró. El residuo obtenido mediante concentración bajo presión reducida se purificó por cromatografía de columna de sílica gel. De este modo, se obtuvo hldrazlna fe/f-butoxicarbonilada como un material como goma de color amarillo pálido (220 mg, 26%). Una 25 solución de ácido clorhídrico 4 M/acetato de etilo (6.0 mi) se adicionó a una solución de acetato de etilo (3.0 mi) de la hldrazlna ferí-butoxicarbonilado preparada. Esta se agitó a temperatura ambiente, durante una hora y media. El sólido precipitado se recolectó por filtración, se lavó con acetato de etilo, y se secó. De este modo, se obtuvo la [2- d¡fluoromet¡l-3-(2-trimetlls¡lanil-etoximetil)-3H-benc¡midazol-5-il]-h¡draz¡na clorhidrato en bruto como un sólido de color amarillo. El producto en bruto se utilizó en reacciones posteriores sin ser purificado.6-Bromo-2-difluoromethyl-1- (2-trimethylslanyl-ethoxymethyl) -1 H -benzimidazole (754 mg, 2.0 mmol), Tris (dibenzylideneacetone) dipaladium (0) (92 mg, 0.1 mmol), 2-dicyclohexylphosphino -2 ', 4', 6'-tri-i-propyl-1,1'-biphenyl (X-PHOS) (143 mg, 0.3 mmol), cesium carbonate (1.3 g, 4.0 mmol), and tert-butyl Carbazate (794 mg, 6.0 mmol) was placed in a flask. After the desalreaclón, the air was replaced with argon. Anhydrous toluene (8.0 ml) was added, and it was stirred at 100 ° C for 20 hours. After cooling to room temperature, the reaction mixture was filtered through Celite, and washed with ethyl acetate. The filtrate was concentrated. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography. Thus, hldrazlna fe / f-butoxycarbonylated was obtained as a pale yellow gum material (220 mg, 26%). A solution of 4M hydrochloric acid / ethyl acetate (6.0 ml) was added to a solution of ethyl acetate (3.0 ml) of the prepared ferro-butoxycarbonylated hldrazlna. This was stirred at room temperature, for an hour and a half. The precipitated solid was collected by filtration, washed with ethyl acetate, and dried. Thus, the [2- dfluoromethyl-3- (2-trimetlls¡lanyl-ethoxymethyl) -3H-benzylmidazol-5-yl] -hrazine hydrochloride was obtained as a solid yellow. The crude product was used in subsequent reactions without being purified.
30 ESI (LC-MS modo positivo) m/z 329 [(M+H)+]30 ESI (LC-MS positive mode) m / z 329 [(M + H) +]
Síntesis del di-tert-butil mesilato del ácido 1-(2-metil-1H-benzo[d]imidazol-5-il)hidrazina-1,2-dicarboxílicoSynthesis of 1- (2-methyl-1 H -benzo [d] imidazol-5-yl) hydrazine-1,2-dicarboxylic acid di-tert-butyl mesylate
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HH
Etapa AStage A
Una solución de la mezcla de 5-yodo-2-metil-1H-benc¡m¡dazol (10 g, 39 mmol), trlmetoxi-metano (200 mi), y clorotrimetllsllano (0.075 mi, 0.59 mmol) se calentó y se agitó a 100°C, durante cinco horas bajo una atmósfera de nitrógeno mientras se separaba por filtración el solvente (una tasa de conversión de la reacción del 97%). La mezcla de reacción se enfrió a 40°C, y a continuación se le adicionó una solución en tetrahidrofurano (0.87 mi, 0.87 mmol) de fe/f-butóxido de potasio. Esta se concentró bajo presión reducida para proveer 1-dimetoximetil-5-yodo-2-metil-1H- bencimidazol en bruto.A solution of the mixture of 5-iodo-2-methyl-1 H -benzamdazole (10 g, 39 mmol), trlmethoxy methane (200 mL), and chlorotrimethylsllane (0.075 mL, 0.59 mmol) was heated and heated. stirred at 100 ° C for five hours under a nitrogen atmosphere while the solvent was filtered off (a reaction conversion rate of 97%). The reaction mixture was cooled to 40 ° C, and then a solution in tetrahydrofuran (0.87 mL, 0.87 mmol) of fe / f-potassium butoxide was added. This was concentrated under reduced pressure to provide crude 1-dimethoxymethyl-5-iodo-2-methyl-1H-benzimidazole.
Una solución en tetrahidrofurano (44 mi, 47 mmol) de cloruro de magnesio ciclohexilo 1.06 M se adicionó a una solución mixta de 1-dimetoximetil-5-yodo-2-metil-1H-bencimidazol en bruto y tetrahidrofurano (79 mi). Esta se agitó a -20°C bajo una atmósfera de nitrógeno, durante dos horas. Una solución de tolueno (40 mi) de di-fe/f-butil azodicarboxilato (10.7 g, 46 mmol) se adicionó a la mezcla de reacción, y esta se agitó bajo una atmósfera de nitrógeno a -20°C, durante una hora y a 0°C, durante otra hora (una tasa de conversión de la reacción de 96%). Una solución acuosa (60 mi) de 15% de cloruro de amonio se adicionó a la mezcla de reacción. Después de la extracción con una solución de isopropilo acetato/heptano (1/1; 50 mi), la capa orgánica se lavó con una solución acuosa (50 mi) de bicarbonato de sodio al 2%. A continuación, se le adicionó 1-metil-pirrolidin-2-ona (15 mi), y esta se concentró bajo presión reducida para proveer una solución en 1-metil-pirrolidin-2-ona (48 mi) de di-fe/f-butil del ácido 1-(1- (dimetoximetil)-2-metil-1H-benzo[d]imidazol-5-il)hidrazina-1,2-dicarboxílico en bruto.A solution in tetrahydrofuran (44 ml, 47 mmol) of 1.06 M cyclohexyl magnesium chloride was added to a mixed solution of crude 1-dimethoxymethyl-5-iodo-2-methyl-1H-benzimidazole and tetrahydrofuran (79 ml). This was stirred at -20 ° C under a nitrogen atmosphere, for two hours. A solution of toluene (40 ml) of di-fe / f-butyl azodicarboxylate (10.7 g, 46 mmol) was added to the reaction mixture, and it was stirred under a nitrogen atmosphere at -20 ° C for one hour. and at 0 ° C, for another hour (a reaction conversion rate of 96%). An aqueous solution (60 ml) of 15% ammonium chloride was added to the reaction mixture. After extraction with a solution of isopropyl acetate / heptane (1/1; 50 ml), the organic layer was washed with an aqueous solution (50 ml) of 2% sodium bicarbonate. Next, 1-methyl-pyrrolidin-2-one (15 ml) was added, and this was concentrated under reduced pressure to provide a solution in 1-methyl-pyrrolidin-2-one (48 ml) of di-fe / 1- (1- (Dimethoxymethyl) -2-methyl-1 H -benzo [d] imidazol-5-yl) hydrazine-1,2-dicarboxylic acid f-butyl.
Se adicionaron acetato de isopropilo (61 mi), agua (0.2 mi), y ácido mesílico (0.87 mi) a la solución de 1-metil- pirrolidin-2-ona (16 mi) de ácido di-fe/f-butil 1-(1-(dimetoximetil)-2-metil-1H-benzo[d]imidazol-5-il)hidrazina-1,2- dicarboxílico en bruto. Esta se agitó a 40°C, durante dos horas. Después de enfriarla a 5°C, el sólido precipitado se recolectó por filtración, y se secó para proveer di-tert-butil mesilato del ácido 1 -(2-metil-1H-benzo[d]imidazol-5- il)hidrazina-1,2-dicarboxílico (4.3 g, 73%).Isopropyl acetate (61 ml), water (0.2 ml), and mesyl acid (0.87 ml) were added to the solution of 1-methyl-pyrrolidin-2-one (16 ml) of di-fe / f-butyl acid 1 - (1- (dimethoxymethyl) -2-methyl-1 H -benzo [d] imidazol-5-yl) hydrazine-1,2-dicarboxylic acid crude. This was stirred at 40 ° C for two hours. After cooling to 5 ° C, the precipitated solid was collected by filtration, and dried to provide 1 - (2-methyl-1 H -benzo [d] imidazol-5-yl) hydrazine- di-tert-butyl mesylate. 1,2-dicarboxylic (4.3 g, 73%).
1H-RMN (CD3OD) 8: 7.87 (1.0H, m), 7.69-7.53 (2.0H, m), 2.84 (3.0H, s), 2.70 (3.0H, s), 1.52-1.47 (18H, m)1H-NMR (CD3OD) 8: 7.87 (1.0H, m), 7.69-7.53 (2.0H, m), 2.84 (3.0H, s), 2.70 (3.0H, s), 1.52-1.47 (18H, m)
1-dimetoximetil-5-yodo-2-metil-1H-bencimidazol en bruto se preparó utilizando cloruro de magnesio en lugar de clorotrimetilsilano en la etapa A (una tasa de conversión de la reacción de 98%).Raw 1-dimethoxymethyl-5-iodo-2-methyl-1H-benzimidazole was prepared using magnesium chloride instead of chlorotrimethylsilane in step A (a reaction conversion rate of 98%).
1-dimetoximetil-5-yodo-2-metil-1H-bencimidazol en bruto se preparó utilizando cloruro de litio en lugar de1-dimethoxymethyl-5-iodo-2-methyl-1H-benzimidazole was prepared using lithium chloride instead of
clorotrimetilsilano en la etapa A (una tasa de conversión de la reacción de 98%).chlorotrimethylsilane in stage A (a reaction conversion rate of 98%).
1-dimetoximetil-5-yodo-2-metil-1H-bencimidazol en bruto se preparó utilizando ácido benzoico en lugar de1-dimethoxymethyl-5-iodo-2-methyl-1H-benzimidazole was prepared using benzoic acid instead of
clorotrimetilsilano en la etapa A (una tasa de conversión de la reacción de 97%).chlorotrimethylsilane in stage A (a reaction conversion rate of 97%).
El di-fe/f-butil del ácido 1-(1-(dimetoximetil)-2-metil-1H-benzo[d]imidazol-5-il)hidrazina-1,2-dicarboxílico en bruto se preparó utilizando una solución en tetrahidrofurano de isopropilo cloruro de magnesio en lugar de una solución en tetrahidrofurano de cloruro de magnesio ciclohexilo en la etapa B (una tasa de conversión de la reacción de 96%).The crude 1- (1- (dimethoxymethyl) -2-methyl-1H-benzo [d] imidazol-5-yl) hydrazine-1,2-dicarboxylic acid di-fe / f-butyl was prepared using a solution in magnesium chloride isopropyl tetrahydrofuran instead of a tetrahydrofuran solution of cyclohexyl magnesium chloride in step B (a reaction conversion rate of 96%).
Síntesis del solvato di-fe/f-butil malato tetrahidrofurano del ácido 1-(2-metil-1H-benzo[d]imidazol-5-il)hidrazina-1,2- dicarboxílicoSynthesis of 1- (2-methyl-1 H -benzo [d] imidazol-5-yl) hydrazine-1,2-dicarboxylic acid solvate di-fe / f-butyl malate tetrahydrofuran
Etapa BStage B
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OHOH
El solvato di-ferí-butll malato tetrahidrofurano del ácido 1-(2-Metil-1H-benzo[d]imidazol-5-il)hidrazina-1,2-dicarboxílico se preparó utilizando tetrahldrofurano, ácido maleico, y heptano en lugar de ácido mesílico y acetato de isopropilo en la etapa B (un rendimiento del 62%).The 1- (2-Methyl-1H-benzo [d] imidazol-5-yl) hydrazine-1,2-dicarboxylic acid solvate di-feri-butll malate tetrahydrofuran was prepared using tetrahydrofuran, maleic acid, and heptane instead of mesyl acid and isopropyl acetate in step B (a yield of 62%).
1H-RMN (CD3OD) 8: 7.77 (1 .OH, m), 7.64-7.53 (2.0H, m), 6.26 (2.0H, s), 3.74-3.71 (4.0H, m), 2.80 (3.0H, s), 1.90- 1.85 (4.OH, m), 1.51-1.48 (18H, m)1H-NMR (CD3OD) 8: 7.77 (1 .OH, m), 7.64-7.53 (2.0H, m), 6.26 (2.0H, s), 3.74-3.71 (4.0H, m), 2.80 (3.0H, s), 1.90-1.85 (4.OH, m), 1.51-1.48 (18H, m)
Etapa 45: Síntesis del áster etílico del ácido 1-(4-metoxi-bencil)-1H-pirrol-2-carboxílico (1502)Step 45: Synthesis of 1- (4-methoxy-benzyl) -1H-pyrrole-2-carboxylic acid ethyl ester (1502)
El hldruro de sodio oleoso al 60% (362 mg) se lavó con hexano, y esta se suspendió en N,N-dimetilformamida (DMF) anhidra (5 mi). Una solución de N,N-d¡met¡lformamida (DMF) (15 mi) del áster etílico del ácido 1 H-pirrol-2- carboxílico (1.05 g) se adicionó gota a gota a la suspensión a 0°C con flujo de argón. La mezcla de reacción se agitó a 25°C, durante una hora, y a continuación 4-metoxicloruro de bencilo (1.5 mi) se le adicionó a 0°C. La mezcla de reacción se agitó a 25°C, durante 10 horas. A continuación, se adicionó hielo (aproximadamente 10 g) a la mezcla de reacción, y esta se extrajo con acetato de etilo (20 mi). La capa orgánica se lavó con una solución acuosa (60 mi) saturada con cloruro de sodio, y a continuación se concentró. El residuo obtenido mediante concentración bajo presión reducida se purificó por cromatografía de columna de sílica gel (hexano/acetato de etilo). De este modo, se obtuvo un material oleoso de color amarillo (1.64 g, 83%).The 60% oily sodium hydride (362 mg) was washed with hexane, and this was suspended in anhydrous N, N-dimethylformamide (DMF) (5 ml). A solution of N, Ndmethylformamide (DMF) (15 ml) of the 1-H-pyrrole-2-carboxylic acid ethyl ester (1.05 g) was added dropwise to the suspension at 0 ° C with argon flow . The reaction mixture was stirred at 25 ° C for one hour, and then benzyl 4-methoxychloride (1.5 ml) was added at 0 ° C. The reaction mixture was stirred at 25 ° C for 10 hours. Then, ice (approximately 10 g) was added to the reaction mixture, and this was extracted with ethyl acetate (20 ml). The organic layer was washed with an aqueous solution (60 ml) saturated with sodium chloride, and then concentrated. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate). In this way, a yellow oily material (1.64 g, 83%) was obtained.
ESI (LC-MS modo positivo) m/z 260 [(M+H)+jESI (LC-MS positive mode) m / z 260 [(M + H) + j
Etapa 46: Síntesis del áster etílico del ácido 4-bromo-1H-pirrol-2-carboxílico (1503)Step 46: Synthesis of 4-bromo-1H-pyrrole-2-carboxylic acid ethyl ester (1503)
Se disolvió el áster etílico del ácido 1H-pirrol-2-carboxílico (10 g) en tetracloruro de carbono (50 mi). Una solución en tetracloruro de carbono (50 mi) de bromo se adicionó gota a gota a esta en hielo, durante 30 minutos. La mezcla de reacción se agitó a 25°C, durante una hora. La suspensión de la mezcla de reacción se adicionó gota a gota a una solución en etanol (100 mi) de etóxido de sodio al 10% en hielo sobre 20 minutos. El solvente se concentró bajo presión reducida. El residuo resultante se diluyó con acetato de etilo (40 mi) y agua (20 mi). La capa orgánica se lavó con una solución acuosa saturada con cloruro de sodio (10 mi), y a continuación se concentró. El residuo obtenido mediante concentración bajo presión reducida se purificó por cromatografía de columna de sílica gel (hexano/acetato de etilo). De este modo, se obtuvo un sólido de color marrón (10 g, 99%).The 1H-pyrrole-2-carboxylic acid ethyl ester (10 g) was dissolved in carbon tetrachloride (50 ml). A solution in carbon tetrachloride (50 ml) of bromine was added dropwise thereto on ice, for 30 minutes. The reaction mixture was stirred at 25 ° C for one hour. The suspension of the reaction mixture was added dropwise to a solution in ethanol (100 ml) of 10% sodium ethoxide in ice over 20 minutes. The solvent was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate (40 ml) and water (20 ml). The organic layer was washed with an aqueous solution saturated with sodium chloride (10 ml), and then concentrated. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate). In this way, a brown solid (10 g, 99%) was obtained.
ESI (LC-MS modo positivo) m/z 218, 220 [(M+H)+]ESI (LC-MS positive mode) m / z 218, 220 [(M + H) +]
Etapa 47: Síntesis del éster etílico del ácido 4,5-dibromo-1-(4-metoxi-bencil)-1H-pirrol-2-carboxílico (1504)Step 47: Synthesis of 4,5-dibromo-1- (4-methoxy-benzyl) -1H-pyrrole-2-carboxylic acid ethyl ester (1504)
OOR
OOR
BrBr
Una solución en N,N-dimetilformamida (DMF) anhidra (9 mi) de N-bromosuccinimida (2.7 g) se adicionó gota a gota a una solución en N,N-dimetilformamida (DMF) anhidra (8 mi) de éster etílico del ácido 1-(4-metoxi-bencil)-1H-pirrol- 5 2-carboxílico (2 g) a 0°C con flujo de argón. La mezcla de reacción se agitó a 0°C, y a continuación se le adicionó agua (20 mi). Después de la extracción con acetato de etilo (30 mi), la capa orgánica se lavó con una solución acuosa saturada con cloruro de sodio (70 mi), y la capa orgánica se concentró bajo presión reducida. El residuo resultante se purificó por cromatografía de columna de sílica gel (hexano/acetato de etilo). De este modo, se obtuvo el éster etílico del ácido 4,5-dibromo-1-(4-metoxi-bencil)-1Hpirrol-2-carboxílico como un material oleoso de color 10 marrón pálido (2.99 g, 92%).A solution in anhydrous N, N-dimethylformamide (DMF) (9 ml) of N-bromosuccinimide (2.7 g) was added dropwise to a solution in anhydrous N, N-dimethylformamide (DMF) (8 ml) of ethyl ester of 1- (4-Methoxy-benzyl) -1H-pyrrole-5-2-carboxylic acid (2 g) at 0 ° C with argon flow. The reaction mixture was stirred at 0 ° C, and then water (20 ml) was added. After extraction with ethyl acetate (30 ml), the organic layer was washed with an aqueous solution saturated with sodium chloride (70 ml), and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate). Thus, 4,5-dibromo-1- (4-methoxy-benzyl) -1H-pyrrol-2-carboxylic acid ethyl ester was obtained as a pale brown oily material (2.99 g, 92%).
ESI (LC-MS modo positivo) m/z 416, 418, 420 [(M+FI)+]ESI (LC-MS positive mode) m / z 416, 418, 420 [(M + FI) +]
Etapa 48: Síntesis de [5-amino-1-(2-metil-1FI-bencimidazol-5-il)-1H-pirazol-4-il]-[4-fenil-1-(tolueno-4-sulfonil)-1H- pirrol-2-il]-metanona (1505)Step 48: Synthesis of [5-amino-1- (2-methyl-1FI-benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [4-phenyl-1- (toluene-4-sulfonyl) - 1H- pyrrol-2-yl] -methanone (1505)
15 Se adicionaron dioxano (1.5 mi) y una solución acuosa (1.5 mi) de bicarbonato de sodio 1 M a [5-amino-1-(2-metil- 1FI-bencimidazol-5-il)-1H-pirazol-4-il]-[4-bromo-1-(tolueno-4-sulfonil) -1H-pirrol-2-il]-metanona (57 mg), complejo cloruro de paladio bis-trifenilfosfina (10 mg), y ácido fenilborónico (37 mg). La mezcla se hizo reaccionar a 140°C en un reactor de microondas durante diez minutos. La mezcla de reacción se diluyó con agua (5 mi), y a continuación se extrajo con acetato de etilo. Las capas orgánicas se combinaron, y se concentraron bajo presión reducida. 20 Después de la purificación por HPLC, el eluato se desaló utilizando el cartucho de PLHCO3 (PolymerLabs), y a continuación se concentró bajo presión reducida. De este modo,15 Dioxane (1.5 ml) and an aqueous solution (1.5 ml) of 1 M sodium bicarbonate were added to [5-amino-1- (2-methyl-1FI-benzimidazol-5-yl) -1H-pyrazole-4- il] - [4-bromo-1- (toluene-4-sulfonyl) -1H-pyrrol-2-yl] -methanone (57 mg), palladium bis-triphenylphosphine chloride complex (10 mg), and phenylboronic acid (37 mg) The mixture was reacted at 140 ° C in a microwave reactor for ten minutes. The reaction mixture was diluted with water (5 ml), and then extracted with ethyl acetate. The organic layers were combined, and concentrated under reduced pressure. After purification by HPLC, the eluate was desalted using the PLHCO3 cartridge (PolymerLabs), and then concentrated under reduced pressure. In this way,
se obtuvo la [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1H-pirazol-4-il]-[4-fenil-1-(tolueno-4-sulfonil) -1 H-pirrol-2-il]- metanona como un polvo de color amarillo pálido (15 mg, 26%).[5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 H -pyrazol-4-yl] - [4-phenyl-1- (toluene-4-sulfonyl) -1 H was obtained -pyrrol-2-yl] - methanone as a pale yellow powder (15 mg, 26%).
ESI (LC-MS modo positivo) m/z 537 [(M+H)+]ESI (LC-MS positive mode) m / z 537 [(M + H) +]
25 Los compuestos de los números 1506 a 1510, y 1591 a 1598 enumerados en la Tabla 33, se sintetizaron como se describe en la Etapa 48.The compounds of Nos. 1506 to 1510, and 1591 to 1598 listed in Table 33, were synthesized as described in Step 48.
o=s=oo = s = o
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1506 1506
- n P"' MH. Q [5-amino-1-(2-metil-1H-bencimidazol-5-il)- 1Hpirazol -4-il]-[1-(4-metoxi-bencil) -4,5-difenil- 1 H-pirrol-2-il] -metanona 579 n P "'MH. Q [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) - 1 Hpyrazol -4-yl] - [1- (4-methoxy-benzyl) -4.5- diphenyl- 1 H -pyrrol-2-yl] -methanone 579
- 1507 1507
- i [5-amino-1-(2-metil-1H-bencimidazol-5-il)- 1Hpirazol -4-il]-[1-(4-metoxi-bencil) -4,5-dipiridin- 3-il-1 H-pirrol -2-il]-metanona 581 i [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hpyrazol -4-yl] - [1- (4-methoxy-benzyl) -4,5-dipyridin-3-yl- 1 H-pyrrole -2-yl] -methanone 581
- 1508 1508
- 0=S=D Ji p í fJH. Y ^aNr [5-amino-1-(2-metil-H-bencimidazol-5-il)- 1Hpirazol -4-il]-[4-(3-cloro-fenil)-1-(tolueno-4- sulfonil)-1 H-pirrol -2-il]-metanona 571, 573 0 = S = D Ji p í fJH. Y ^ aNr [5-amino-1- (2-methyl-H-benzimidazol-5-yl) -1Hpirazol -4-yl] - [4- (3-chloro-phenyl) -1- (toluene-4-sulfonyl ) -1 H-pyrrole -2-yl] -methanone 571, 573
- 1509 1509
- 0=5=0 rN 0 [5-amino-1-(2-metil-1H-bencimidazol-5-il)- 1Hpirazol -4-il]-[4-(4-fluoro-fenil)-1-(tolueno-4- sulfonil)-1 H-pirrol -2-il]-metanona 555 0 = 5 = 0 rN 0 [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) - 1 Hpyrazol -4-yl] - [4- (4-fluoro-phenyl) -1- (toluene -4- sulfonyl) -1 H-pyrrole -2-yl] -methanone 555
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1510 1510
- 0 C=S=5 1 ^ v [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol -4- il]-[4-(3-fluoro-fenil)-1-(tolueno-4- sulfonil)-1 H-pirrol -2- il]-metanona 555 0 C = S = 5 1 ^ v [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpirazol -4-yl] - [4- (3-fluoro-phenyl) - 1- (toluene-4-sulfonyl) -1 H-pyrrole -2-yl] -methanone 555
- 1591 1591
- —í"i [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4- il]-[1-(4-metoxi-bencil)-4-(4- metoxi-fenil)-1 H-pirrol-2-il]- metanona 533 —Í "i [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4- yl] - [1- (4-methoxy-benzyl) -4- (4- methoxy-phenyl) -1 H-pyrrol-2-yl] - methanone 533
- 1592 1592
- i ' a,. 0 / [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4- il]-[1-(4-metoxi-bencil)-4-(3- metoxi-fenil)-1 H-pirrol-2-il]- metanona 533 i 'a ,. 0 / [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpyrazol- 4- yl] - [1- (4-methoxy-benzyl) -4- (3- methoxy- phenyl) -1 H-pyrrol-2-yl] - methanone 533
- 1593 1593
- °;a dXv'wV ' M V-&" H F [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4- il]-[4,5-bis-(3-fluoro-fenil)-1-(4- metoxi-bencil)-1H-pirrol- 2-il]-metanona 615 °; to dXv'wV 'M V- & "HF [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpirazol-4- yl] - [4,5-bis- (3-Fluoro-phenyl) -1- (4- methoxy-benzyl) -1H-pyrrole-2-yl] -methanone 615
- 1594 1594
- i V [5-amino-1-(2-metil-1 H-bencimidazol-5-il)-1 Hpirazol- 4- il]-[4-(5-fluoro-2-metoxi-fenil)-1-(4- metoxi-bencil)-1 H- pirrol-2-il]-metanona 551 i V [5-amino-1- (2-methyl-1 H-benzimidazol-5-yl) -1 Hpyrazol- 4- yl] - [4- (5-fluoro-2-methoxy-phenyl) -1- ( 4- methoxy-benzyl) -1 H- pyrrol-2-yl] -methanone 551
- Compuesto No. Compound No.
- Estructura Nombre del compuesto m/z Structure Name of compound m / z
- 1595 1595
- / Q JyHr [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpirazol- 4- il]-[1-(4-metoxi-bencil)-4,5-bis-(4- metoxi-fenil)-1 H- pirrol-2-il]-metanona 639 / Q JyHr [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 Hpirazol-4- yl] - [1- (4-methoxy-benzyl) -4,5-bis- (4 - methoxy-phenyl) -1 H- pyrrol-2-yl] -methanone 639
- 1596 1596
- / O [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpirazol- 4- il]-[4-(2,4-difluoro-fenil)-1-(4- metoxi-bencil)-1 H-pirrol- 2-il]-metanona 539 / O [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1Hyrazol- 4- yl] - [4- (2,4-difluoro-phenyl) -1- (4- methoxy- Benzyl) -1 H-pyrrole-2-yl] -methanone 539
- 1597 1597
- r f [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpirazol- 4- il]-[1-(4-metoxi-bencil)-4-(4- trifluorometoxi-fenil)-1 H- pirrol-2-il]-metanona 589 rf [5-amino-1- (2-methyl-1H-benzimidazol-5-yl) -1-pyrazol- 4- yl] - [1- (4-methoxy-benzyl) -4- (4- trifluoromethoxy-phenyl) - 1 H- pyrrol-2-yl] -methanone 589
- 1598 1598
- y vXCr ^ H [5-amino-1-(2-metil-1H-bencimidazol-5-il)-1Hpirazol- 4- il]-[1-(4-metoxi-bencil)-4,5-bis-(3- metoxi-fenil)-1 H- pirrol-2-il]-metanona 439 and vXCr ^ H [5-amino-1- (2-methyl-1 H -benzimidazol-5-yl) -1 Hpirazol-4- yl] - [1- (4-methoxy-benzyl) -4,5-bis- ( 3- methoxy-phenyl) -1 H- pyrrole-2-yl] -methanone 439
[Ejemplos 201: Síntesis de [5-amino-1-(2-metil-1H-benc¡m¡dazol-5-il)-1H-pirazol-4-il]-(4,5-d¡bromo-1H-p¡rrol-2-il)- metanona][Examples 201: Synthesis of [5-amino-1- (2-methyl-1H-benzyldazol-5-yl) -1H-pyrazol-4-yl] - (4,5-dromobrom-1H -prolrol-2-yl) - methanone]
55
Se disolvió [5-amino-1-(2-met¡MH-bencimidazol-5-¡l)-1H-p¡razol-4-¡l]-[4,5-dibromo-1-(4-metox¡-bencil)-1H-p¡rrol- 2-¡l]- metanona (317 mg) en acetato de etilo/ácido sulfúrico (4/1; 5 mi). Esta se agitó a 80°C, durante cuatro horas. El pH de la mezcla de reacción se ajustó a 11 (básico) utilizando una solución acuosa de hidróxido de sodio 5 M mientras se enfriaba en hielo. La mezcla de reacción se extrajo con acetato de etilo/tetrahidrofurano (THF) (10 mi). La capa 10 orgánica se lavó con una solución acuosa saturada con cloruro de sodio (5 mi), y la capa orgánica se concentró bajo presión reducida. El residuo resultante se purificó por cromatografía de columna de sílica gel (diclorometano/metanol).[5-Amino-1- (2-metHM-benzimidazol-5-α) -1 H -pyrazol-4-α] - [4,5-dibromo-1- (4-methoxy) -benzyl) -1H-pyrrol-2-l] - methanone (317 mg) in ethyl acetate / sulfuric acid (4/1; 5 ml). This was stirred at 80 ° C for four hours. The pH of the reaction mixture was adjusted to 11 (basic) using a 5M aqueous solution of sodium hydroxide while cooling on ice. The reaction mixture was extracted with ethyl acetate / tetrahydrofuran (THF) (10 ml). The organic layer 10 was washed with an aqueous solution saturated with sodium chloride (5 mL), and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol).
De este modo, se obtuvo un sólido de color marrón (135 mg, 54%).Thus, a brown solid (135 mg, 54%) was obtained.
1H-RMN (DMSO-De) 6: 12.88 (1H, s), 12.46 (1H, s), 8.19 (1H, s), 7.63 (1H, d, J = 8 7 Hz) 7 56-7 54 (1H m) 7 27- 7.26 (3H, m), 6.90 (1H, t, J = 14.2 Hz), 2.53 (3H, s)1H-NMR (DMSO-De) 6: 12.88 (1H, s), 12.46 (1H, s), 8.19 (1H, s), 7.63 (1H, d, J = 8 7 Hz) 7 56-7 54 (1H m) 7 27- 7.26 (3H, m), 6.90 (1H, t, J = 14.2 Hz), 2.53 (3H, s)
ESI (LC-MS modo positivo) m/z 463, 465, 467 [(M+H)+]ESI (LC-MS positive mode) m / z 463, 465, 467 [(M + H) +]
5 [Ejemplos 202 y 203]5 [Examples 202 and 203]
Los compuestos de los Ejemplos 202, 203, y 240-246 enumerados en la Tabla 34, se sintetizaron como se describe en Ejemplo 201.The compounds of Examples 202, 203, and 240-246 listed in Table 34, were synthesized as described in Example 201.
Tabla 34Table 34
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 202 202
- [5-ami no-1-(2-metll- 1H-bencimldazol- 5- il)-1 Hpirazol- 4-II] - (4,5-difenil- 1 H-pirrol- 2-¡l)-metanona 459 1H-RMN (CD30D) 6: 8.22 (1H, s), 7.73-7.64 (3H, m), 7.60-7.51 (2H, m), 7.45-7.38 (3H, m), 7.37-7.18 (9H, m), 2.61 (3H, s). [5-ami no-1- (2-metll- 1H-benzimldazol- 5- il) -1 Hpyrazol- 4-II] - (4,5-diphenyl- 1 H -pyrrole-2-¡l) -methanone 459 1H-NMR (CD30D) 6: 8.22 (1H, s), 7.73-7.64 (3H, m), 7.60-7.51 (2H, m), 7.45-7.38 (3H, m), 7.37-7.18 (9H, m) , 2.61 (3H, s).
- 203 203
- O [5-ami no-1-(2-metil- 1 H-bencimidazol- 5- il)-1 Hpirazol- 4-II] - (4,5-dipiridln-3-¡l-1H- pirrol-2-il)-metanona 461 1H-RMN (DMSO-D6) 6 : 12.39 (1H, s), 8.56 (1H, dd, J = 7.9, 2.1 Hz), 8.52 (1H, dd, J = 4.7, 1.1Hz), 8 43(1 H, dd, J = 4.7, 1.6 Hz), 8 38 (1H, s), 7.81 (1H, dt, J = 7.9, 1.9 Hz), 7.72 (1H, dt, J = 8.0, 2.0 Hz), 7.63-7.59 (2H, m), 7.42 (1H, t, J = 3.7 Hz), 7.36 (1H, dd, J = 8.5, 3.7 Hz), 7.30 (1H, dd, J = 8.6, 2.0 Hz), 6.98 (2H, brs), 2.54 (3H, s). O [5-ami no-1- (2-methyl- 1 H -benzimidazol-5- yl) -1 Hpirazol-4-II] - (4,5-dipyridln-3-l-1H- pyrrole-2- il) -methanone 461 1H-NMR (DMSO-D6) 6: 12.39 (1H, s), 8.56 (1H, dd, J = 7.9, 2.1 Hz), 8.52 (1H, dd, J = 4.7, 1.1Hz), 8 43 (1 H, dd, J = 4.7, 1.6 Hz), 8 38 (1H, s), 7.81 (1H, dt, J = 7.9, 1.9 Hz), 7.72 (1H, dt, J = 8.0, 2.0 Hz ), 7.63-7.59 (2H, m), 7.42 (1H, t, J = 3.7 Hz), 7.36 (1H, dd, J = 8.5, 3.7 Hz), 7.30 (1H, dd, J = 8.6, 2.0 Hz) , 6.98 (2H, brs), 2.54 (3H, s).
- 240 240
- U - y [5-amino-1-(2-metil- 1 H-bencimidazol-5-il)- 1 Hpirazol- 4-il]-[4-(4- metoxifenil)- 1 H-pirrol- 2-il]-metanona 413 11.9 (1H, brs), 7.64-7.62 (2H, m), 7.56 (1H, m), 7.51 (1H, m), 7.33-7.31 (3H, m), 7.27-7.23 (1H, m), 6.96 (1H, m), 6.90 (2H, m), 6.75-6.73 (1H, m), 3.82 (3H, s), 2.60 (3H, s) U - and [5-amino-1- (2-methyl- 1 H -benzimidazol-5-yl) -1 Hpirazol-4-yl] - [4- (4- methoxyphenyl) -1 H-pyrrole-2-yl ] -methanone 413 11.9 (1H, brs), 7.64-7.62 (2H, m), 7.56 (1H, m), 7.51 (1H, m), 7.33-7.31 (3H, m), 7.27-7.23 (1H, m ), 6.96 (1H, m), 6.90 (2H, m), 6.75-6.73 (1H, m), 3.82 (3H, s), 2.60 (3H, s)
- 241 241
- .H F i": * [5-ami no-1 -(2-metil- 1 H-bencimidazol-5-il)- 1 Hpirazol-4-il]-[4-(3- metoxifenil)- 1 H-pirrol- 2-il]-metanona 413 11.9 (1H, brs), 7.69-7.62 (2H, m), 7.56 (1H, m), 7.51 (1H, m), 7.33-7.31 (3H, m), 7.27-7.23 (1H, m), 6.96 (1H, m), 6.90 (2H, m), 6.75-6.73 (1H, m), 3.82 (3H, s), 2.60 (3H, s) .HF i ": * [5-ami no-1 - (2-methyl- 1 H -benzimidazol-5-yl) - 1 Hpirazol-4-yl] - [4- (3- methoxyphenyl) - 1 H-pyrrole - 2-yl] -methanone 413 11.9 (1H, brs), 7.69-7.62 (2H, m), 7.56 (1H, m), 7.51 (1H, m), 7.33-7.31 (3H, m), 7.27-7.23 (1H, m), 6.96 (1H, m), 6.90 (2H, m), 6.75-6.73 (1H, m), 3.82 (3H, s), 2.60 (3H, s)
- 242 242
- P-AvT! wv U [5-ami no-1 -(2-metil- 1H-bencimidazol- 5- il)-1 Hpirazol- 4-il]-[4,5- bis-(3- fluoro-fenil)- 1 H-pirrol-2-ilj- metanona 495 7.67 (1H, m), 7.41-7.28 (3H, m), 7.25- 7.23 (2H, m), 7.16-7.14 (2H, m), 7.10- 7.05 (2H, m), 6.99-6.95 (1H, m), 2.65 (3H, s) P-AvT! wv U [5-ami no-1 - (2-methyl- 1 H -benzimidazol-5- yl) -1 Hpirazol-4-yl] - [4,5-bis- (3- fluoro-phenyl) - 1 H- pyrrol-2-yl-methanone 495 7.67 (1H, m), 7.41-7.28 (3H, m), 7.25- 7.23 (2H, m), 7.16-7.14 (2H, m), 7.10- 7.05 (2H, m) , 6.99-6.95 (1H, m), 2.65 (3H, s)
55
1010
15fifteen
20twenty
2525
- Ejemplo Example
- Estructura Nombre del compuesto m/z 1H-RMN Structure Name of compound m / z 1H-NMR
- 243 243
- II-. Js * r~ ■'-o-r [5-amino-1-(2-metil-1 H- bencimidazol- 5-il)-1 Hpirazol- 4-¡l]-[4,5-bis-(4- metoxi-fenil)- 1 H-pi rrol- 2-il]-metanona 519 8.19 (1H, m), 7.66-7.64 (2H, m), 7.38-7.34 (3H, m), 7.25-7.23 (2H, m), 7.14 (1H, m), 6.91-6.84 (4H, s), 3.80 (3H, s), 3.76 (3H, s), 2.61 (3H, s) II-. Js * r ~ ■ '-or [5-amino-1- (2-methyl-1 H- benzimidazol- 5-yl) -1 Hpyrazol- 4-α] - [4,5-bis- (4- methoxy -phenyl) - 1 H-pi rrol-2-yl] -methanone 519 8.19 (1H, m), 7.66-7.64 (2H, m), 7.38-7.34 (3H, m), 7.25-7.23 (2H, m) , 7.14 (1H, m), 6.91-6.84 (4H, s), 3.80 (3H, s), 3.76 (3H, s), 2.61 (3H, s)
- 244 244
- [5-amlno-l-(2-metil-1 H- bencimidazol- 5-¡l)-1 Hpirazol- 4-¡l]-[4-(2,4- difluoro-fenil)- 1 H-p¡rrol- 2-¡l]-metanona 419 8.30 (1H, m), 7.96-7.89 (1H, m), 7.69 (2H, m), 7.47-7.45 (2H, m), 7.42-7.39 (1H, m), 7.26-7.21 (1H, m), 7.12-7.08 (1H, m), 2.60 (3H, s) [5-amlno-l- (2-methyl-1 H- benzimidazol- 5-l) -1 Hpirazol- 4-l] - [4- (2,4- difluoro-phenyl) - 1 Hprrol- 2-¡] -methanone 419 8.30 (1H, m), 7.96-7.89 (1H, m), 7.69 (2H, m), 7.47-7.45 (2H, m), 7.42-7.39 (1H, m), 7.26 -7.21 (1H, m), 7.12-7.08 (1H, m), 2.60 (3H, s)
- 245 245
- [5-am¡no-1-(2-metil-1 H- bencimidazol-5-il)-1 Hpirazol- 4-¡l]-[4-(4-trifluorometox¡- fenil)- 1 H-pirrol-2-il]- metanona 467 12.5 (1H, brs), 11.9 (1H, brs), 8.39 (1H, m), 7.89-7.87 (2H, m), 7.64-7.55 (4H, m), 7.33-7.31 (3H, m), 6.91-6.85 (2H, m), 2.54 (3H, s) [5-amine-1- (2-methyl-1 H- benzimidazol-5-yl) -1 Hpyrazol- 4-yl] - [4- (4-trifluoromethoxy-phenyl) - 1 H -pyrrole- 2-yl] - methanone 467 12.5 (1H, brs), 11.9 (1H, brs), 8.39 (1H, m), 7.89-7.87 (2H, m), 7.64-7.55 (4H, m), 7.33-7.31 ( 3H, m), 6.91-6.85 (2H, m), 2.54 (3H, s)
- 246 246
- -*■ XatT [5-am¡no-1-(2-metil-1 H- bencimidazol-5-il)-1 Hpirazol- 4-¡l]-[4,5-bls-(3- metoxi-fenll)- 1 H-p¡rrol- 2-¡l]-metanona 519 12.5 (1H, brs), 11.9 (1H, brs), 7.65-7.63 (1H, m), 7.58-7.55 (1H, m), 7.31-7.28 (1H, m), 7.25-7.18 (3H, m), 7.07 (1H, m), 6.96-6.86 (6H, m), 6.80-6.78 (1H, m), 3.73 (3H, s), 3.69 (3H, s), 2.53 (3H, s) - * ■ XatT [5-amine-1- (2-methyl-1 H- benzimidazol-5-yl) -1 Hpyrazol- 4-α] - [4,5-bls- (3- methoxy-fenll ) - 1 Hp¡rol-2-l] -methanone 519 12.5 (1H, brs), 11.9 (1H, brs), 7.65-7.63 (1H, m), 7.58-7.55 (1H, m), 7.31-7.28 (1H, m), 7.25-7.18 (3H, m), 7.07 (1H, m), 6.96-6.86 (6H, m), 6.80-6.78 (1H, m), 3.73 (3H, s), 3.69 (3H , s), 2.53 (3H, s)
Métodos de ensayo farmacológicosPharmacological test methods
1. Actividad inhibidora contra la enzima FGFR11. Inhibitory activity against the enzyme FGFR1
La actividad inhibidora del FGFR1 se midió basándose en la actividad para inhibir la fosforilación del péptido biotinilado EGPWLEEEEEAYGWMDF por la enzima humana del FGFR1 (Carna Biosciences, cat. 08-133). Se detectaron péptidos biotinilados fosforilados mediante la medición de fluorescencia resuelta en el tiempo utilizando un anticuerpo anti-fosfotirosina ligado a criptato de europio y una estreptavidina a la que XL665, un derivado de aloficocianina, está vinculado. La concentración inhibitoria 50% (IC50) se calculó basándose en la tasa inhibidora contra el grupo de control sin sustancias de ensayo.The inhibitory activity of FGFR1 was measured based on the activity to inhibit phosphorylation of the biotinylated peptide EGPWLEEEEEAYGWMDF by the human enzyme of FGFR1 (Carna Biosciences, cat. 08-133). Phosphorylated biotinylated peptides were detected by measurement of time-resolved fluorescence using an anti-phosphotyrosine antibody linked to europium cryptate and a streptavidin to which XL665, an allophycocyanin derivative, is linked. The 50% inhibitory concentration (IC50) was calculated based on the inhibitory rate against the control group without test substances.
2. Actividad inhibidora contra la enzima del FGFR22. FGFR2 enzyme inhibitory activity
La actividad inhibidora del FGFR2 se midió basándose en la actividad para inhibir la fosforilación del péptido biotinilado EGPWLEEEEEAYGWMDF por la enzima humana del FGFR2 preparada utilizando un sistema de expresión de baculovirus. Los péptidos biotinilados fosforilados se detectaron mediante la medición de fluorescencia resuelta en el tiempo utilizando un anticuerpo anti-fosfotirosina ligado a criptato de europio y una estreptavidina a la que XL665, un derivado de aloficocianina, está unido. La concentración inhibitoria 50% (IC50) se calculó basándose en la tasa inhibidora contra el grupo de control sin sustancias de ensayo.The inhibitory activity of FGFR2 was measured based on the activity to inhibit phosphorylation of the biotinylated peptide EGPWLEEEEEAYGWMDF by the human enzyme of FGFR2 prepared using a baculovirus expression system. The biotinylated phosphorylated peptides were detected by the measurement of time-resolved fluorescence using an anti-phosphotyrosine antibody linked to europium cryptate and a streptavidin to which XL665, an allophycocyanin derivative, is bound. The 50% inhibitory concentration (IC50) was calculated based on the inhibitory rate against the control group without test substances.
3. Actividad inhibidora contra la enzima del FGFR33. FGFR3 enzyme inhibitory activity
Actividad inhibidora del FGFR3 se midió basándose en la actividad para inhibir la fosforilación del péptido biotinilado EGPWLEEEEEAYGWMDF por la enzima humana del FGFR3 (Carna Biosciences, cat. 08-135). Los péptidos biotinilados fosforiladas se detectaron mediante la medición de fluorescencia resuelta en el tiempo utilizando un anticuerpo anti-fosfotirosina ligado a criptato de europio y un estreptavidina a la que XL665, un derivado de aloficocianina, está unido. La concentración inhibitoria 50% (IC50) se calculó basándose en la tasa Inhibidora contra el grupo de control sin sustancias de ensayo.FGFR3 inhibitory activity was measured based on the activity to inhibit phosphorylation of the biotinylated peptide EGPWLEEEEEAYGWMDF by the human enzyme of FGFR3 (Carna Biosciences, cat. 08-135). The biotinylated phosphorylated peptides were detected by measurement of time-resolved fluorescence using an anti-phosphotyrosine antibody linked to europium cryptate and a streptavidin to which XL665, an allophycocyanin derivative, is bound. The 50% inhibitory concentration (IC50) was calculated based on the Inhibitory rate against the control group without test substances.
Resultados de la pruebaTest results
Los compuestos que tienen una actividad de inhibición FGFR1 (IC50 de 0.3 p,M o menos):Compounds that have an FGFR1 inhibition activity (IC50 of 0.3 p, M or less):
Ejemplos 1-14, 16-18, 23-25, 27-32, 35-62, 64-87, 89-108, 110, 112-125, 130-161, 163-175, 177-191, y 192-201Examples 1-14, 16-18, 23-25, 27-32, 35-62, 64-87, 89-108, 110, 112-125, 130-161, 163-175, 177-191, and 192- 201
Los compuestos que tienen una actividad de inhibición del FGFR2 (IC5o de 0.3 pM o menos): Ejemplos 1-14, 16-62, 64-108, 110, 112-126, 128-150, 152-161, 163-191, y 192-201 Compuestos que tienen una actividad de inhibición del FGFR3 (IC50 de 0.3 pM o menos): Ejemplos 1-3, 5-9, 12-13, 25, 27-29, 32, 36, 38-50, 52-54, 56, 61, 64-67, 69-72, 5 74-81, 85-87, 89, 91-100, 102-108, 110, 112-121, 123-125, 132-150, 152-161, 163-169, 174-176, 178, 180-187, 189-Compounds that have an inhibition activity of FGFR2 (IC5o of 0.3 pM or less): Examples 1-14, 16-62, 64-108, 110, 112-126, 128-150, 152-161, 163-191, and 192-201 Compounds having an FGFR3 inhibition activity (IC50 of 0.3 pM or less): Examples 1-3, 5-9, 12-13, 25, 27-29, 32, 36, 38-50, 52 -54, 56, 61, 64-67, 69-72, 5 74-81, 85-87, 89, 91-100, 102-108, 110, 112-121, 123-125, 132-150, 152- 161, 163-169, 174-176, 178, 180-187, 189-
191, 192, y 194-200191, 192, and 194-200
Tabla 35Table 35
- Ejemplo Example
- FGFR1 FGFR2 FGFR3 FGFR1 FGFR2 FGFR3
- 1 one
- 0.0050 0.023 0.018 0.0050 0.023 0.018
- 3 3
- 0.0053 0.0055 0.013 0.0053 0.0055 0.013
- 5 5
- 0.028 0.0056 0.038 0.028 0.0056 0.038
- 6 6
- 0.0027 0.0032 0.0054 0.0027 0.0032 0.0054
- 7 7
- 0.0030 0.0043 0.0067 0.0030 0.0043 0.0067
- 12 12
- 0.031 0.0085 0.50 0.031 0.0085 0.50
- 16 16
- 0.042 0.031 0.36 0.042 0.031 0.36
- 21 twenty-one
- 0.46 0.064 50 0.46 0.064 50
- 27 27
- 0.030 0.0054 0.0031 0.030 0.0054 0.0031
- 28 28
- 0.099 0.021 0.21 0.099 0.021 0.21
- 29 29
- 0.093 0.019 0.35 0.093 0.019 0.35
- 38 38
- 0.015 0.023 0.077 0.015 0.023 0.077
- 39 39
- 0.010 0.015 0.046 0.010 0.015 0.046
- 40 40
- 0.00081 0.012 0.0037 0.00081 0.012 0.0037
- 42 42
- 0.0096 0.023 0.034 0.0096 0.023 0.034
- 43 43
- 0.017 0.017 0.070 0.017 0.017 0.070
- 47 47
- 0.0027 0.0043 0.0054 0.0027 0.0043 0.0054
- 48 48
- 0.030 0.0089 0.11 0.030 0.0089 0.11
- 50 fifty
- 0.042 0.026 0.15 0.042 0.026 0.15
- 52 52
- 0.016 0.0086 0.21 0.016 0.0086 0.21
- 53 53
- 0.043 0.021 0.15 0.043 0.021 0.15
- 54 54
- 0.089 0.042 0.19 0.089 0.042 0.19
- 56 56
- 0.051 0.034 0.18 0.051 0.034 0.18
- 57 57
- 0.26 0.086 0.58 0.26 0.086 0.58
- Ejemplo Example
- FGFR1 FGFR2 FGFR3 FGFR1 FGFR2 FGFR3
- 60 60
- 0.077 0.022 0.32 0.077 0.022 0.32
- 62 62
- 0.035 0.016 0.36 0.035 0.016 0.36
- 64 64
- 0.022 0.012 0.16 0.022 0.012 0.16
- 66 66
- 0.025 0.048 0.043 0.025 0.048 0.043
- 67 67
- 0.029 0.025 0.082 0.029 0.025 0.082
- 68 68
- 0.23 0.20 0.40 0.23 0.20 0.40
- 69 69
- 0.023 0.016 0.060 0.023 0.016 0.060
- 71 71
- 0.060 0.027 0.13 0.060 0.027 0.13
- 72 72
- 0.045 0.021 0.082 0.045 0.021 0.082
- 73 73
- 0.076 0.036 0.80 0.076 0.036 0.80
- 74 74
- 0.050 0.026 0.23 0.050 0.026 0.23
- 75 75
- 0.043 0.022 0.086 0.043 0.022 0.086
- 79 79
- 0.018 0.010 0.027 0.018 0.010 0.027
- 81 81
- 0.018 0.012 0.045 0.018 0.012 0.045
- 82 82
- 0.024 0.0083 0.37 0.024 0.0083 0.37
- 83 83
- 0.057 0.014 0.67 0.057 0.014 0.67
- 85 85
- 0.022 0.0055 0.094 0.022 0.0055 0.094
- 87 87
- 0.062 0.014 0.090 0.062 0.014 0.090
- 90 90
- 0.075 0.040 0.38 0.075 0.040 0.38
- 91 91
- 0.039 0.018 0.077 0.039 0.018 0.077
- 92 92
- 0.009 0.0062 0.032 0.009 0.0062 0.032
- 93 93
- 0.043 0.039 0.015 0.043 0.039 0.015
- 96 96
- 0.033 0.038 0.068 0.033 0.038 0.068
- 98 98
- 0.011 0.017 0.065 0.011 0.017 0.065
- 102 102
- 0.048 0.039 0.16 0.048 0.039 0.16
- 104 104
- 0.036 0.031 0.14 0.036 0.031 0.14
- 107 107
- 0.0069 0.0084 0.018 0.0069 0.0084 0.018
- 114 114
- 0.00032 0.012 0.012 0.00032 0.012 0.012
- 115 115
- 0.00067 0.0085 0.030 0.00067 0.0085 0.030
- Ejemplo Example
- FGFR1 FGFR2 FGFR3 FGFR1 FGFR2 FGFR3
- 121 121
- 0.087 0.11 0.13 0.087 0.11 0.13
- 124 124
- 0.011 0.012 0.041 0.011 0.012 0.041
- 126 126
- 0.39 0.26 2.1 0.39 0.26 2.1
- 127 127
- 0.98 0.51 5.5 0.98 0.51 5.5
- 131 131
- 0.21 0.067 9.8 0.21 0.067 9.8
- 132 132
- 0.0014 0.0034 0.0035 0.0014 0.0034 0.0035
- 133 133
- 0.0051 0.026 0.19 0.0051 0.026 0.19
- 134 134
- 0.0020 0.012 0.035 0.0020 0.012 0.035
- 137 137
- 0.0064 0.019 0.026 0.0064 0.019 0.026
- 138 138
- 0.0042 0.006 0.0056 0.0042 0.006 0.0056
- 139 139
- 0.0085 0.029 0.018 0.0085 0.029 0.018
- 141 141
- 0.0025 0.0040 0.0016 0.0025 0.0040 0.0016
- 145 145
- 0.0038 0.0091 0.010 0.0038 0.0091 0.010
- 149 149
- 0.024 0.20 0.28 0.024 0.20 0.28
- 150 150
- 0.0029 0.065 0.079 0.0029 0.065 0.079
- 151 151
- 0.082 0.32 0.92 0.082 0.32 0.92
- 153 153
- 0.0079 0.011 0.036 0.0079 0.011 0.036
- 154 154
- 0.066 0.038 0.13 0.066 0.038 0.13
- 155 155
- 0.0018 0.0063 0.0012 0.0018 0.0063 0.0012
- 157 157
- 0.0016 0.0048 0.012 0.0016 0.0048 0.012
- 158 158
- 0.0014 0.0046 0.010 0.0014 0.0046 0.010
- 159 159
- 0.070 0.028 0.19 0.070 0.028 0.19
- 163 163
- 0.018 0.0036 0.019 0.018 0.0036 0.019
- 164 164
- 0.0030 0.010 0.0084 0.0030 0.010 0.0084
- 166 166
- 0.040 0.015 0.080 0.040 0.015 0.080
- 168 168
- 0.048 0.021 0.079 0.048 0.021 0.079
- 169 169
- 0.03 0.015 0.14 0.03 0.015 0.14
- 170 170
- 0.15 0.056 0.95 0.15 0.056 0.95
- 177 177
- 0.12 0.11 0.38 0.12 0.11 0.38
- Ejemplo Example
- FGFR1 FGFR2 FGFR3 FGFR1 FGFR2 FGFR3
- 178 178
- 0.033 0.020 0.077 0.033 0.020 0.077
- 182 182
- 0.060 0.029 0.18 0.060 0.029 0.18
- 185 185
- 0.0055 0.0040 0.029 0.0055 0.0040 0.029
- 187 187
- 0.046 0.016 0.25 0.046 0.016 0.25
- 188 188
- 0.091 0.026 1.3 0.091 0.026 1.3
- 189 189
- 0.038 0.0076 0.10 0.038 0.0076 0.10
- 190 190
- 0.034 0.0055 0.094 0.034 0.0055 0.094
- 192 192
- 0.031 0.020 0.11 0.031 0.020 0.11
- 193 193
- 0.14 0.078 0.37 0.14 0.078 0.37
- 196 196
- 0.0029 0.0094 0.13 0.0029 0.0094 0.13
- 198 198
- 0.021 0.020 0.090 0.021 0.020 0.090
- 199 199
- 0.027 0.018 0.12 0.027 0.018 0.12
- 200 200
- 0.056 0.021 0.068 0.056 0.021 0.068
- 201 201
- 0.26 0.066 1.4 0.26 0.066 1.4
- 203 203
- 1.7 0.393 1.8 1.7 0.393 1.8
- 204 204
- 0.091 0.057 0.37 0.091 0.057 0.37
- 207 207
- 3.6 1.9 7.9 3.6 1.9 7.9
- 210 210
- 0.092 0.037 0.33 0.092 0.037 0.33
- 213 213
- 0.045 0.026 0.15 0.045 0.026 0.15
- 222 222
- 0.053 0.017 0.21 0.053 0.017 0.21
- 225 225
- 0.053 0.028 0.26 0.053 0.028 0.26
- 229 229
- 0.036 0.010 0.35 0.036 0.010 0.35
- 232 232
- 0.056 0.22 0.26 0.056 0.22 0.26
- 233 233
- 0.210 0.35 0.88 0.210 0.35 0.88
- 239 239
- 2.8 0.538 4.0 2.8 0.538 4.0
- 240 240
- 0.85 0.18 3.18 0.85 0.18 3.18
- 249 249
- 0.038 0.022 0.082 0.038 0.022 0.082
- 250 250
- 0.095 0.040 0.32 0.095 0.040 0.32
- 251 251
- 0.077 0.032 0.23 0.077 0.032 0.23
[Aplicabilidad industrial][Industrial Applicability]
La presente invención y la descripción proporcionan compuestos que tienen una actividad de inhibición de la familia de quinasas FGFR. Adicionalmente, la presente invención y la descripción proporcionan agentes farmacéuticos para la prevención y/o tratamiento de cánceres (por ejemplo, cáncer de mama, leucemia mielocítica aguda, cáncer de 5 páncreas, cáncer de vejiga, cáncer de próstata, cáncer de esófago, angiogénesis, cáncer de estómago, cáncer de cuerpo uterino, cáncer de ovario, tumor cerebral incluyendo glioblastoma, cáncer de colon, mleloma múltiple, carcinoma hepatocelular, cáncer de pulmón incluyendo cáncer de pulmón de células pequeñas y de células no pequeñas, y cáncer de tiroides).The present invention and description provide compounds that have an inhibition activity of the FGFR kinase family. Additionally, the present invention and the description provide pharmaceutical agents for the prevention and / or treatment of cancers (eg, breast cancer, acute myelocytic leukemia, 5 pancreas cancer, bladder cancer, prostate cancer, esophageal cancer, angiogenesis , stomach cancer, uterine body cancer, ovarian cancer, brain tumor including glioblastoma, colon cancer, multiple myeloma, hepatocellular carcinoma, lung cancer including small cell and non-small cell lung cancer, and thyroid cancer) .
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| EP (1) | EP2471786B1 (en) |
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| KR (1) | KR101529767B1 (en) |
| CN (1) | CN102574836B (en) |
| AR (1) | AR084370A1 (en) |
| AU (1) | AU2010279930B2 (en) |
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| SI (1) | SI2471786T1 (en) |
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| EP3822273B1 (en) | 2012-06-13 | 2024-04-10 | Incyte Holdings Corporation | Substituted tricyclic compounds as fgfr inhibitors |
| RS62233B1 (en) | 2012-07-11 | 2021-09-30 | Blueprint Medicines Corp | Inhibitors of the fibroblast growth factor receptor |
| WO2014026125A1 (en) | 2012-08-10 | 2014-02-13 | Incyte Corporation | Pyrazine derivatives as fgfr inhibitors |
| ES2643571T3 (en) * | 2012-09-27 | 2017-11-23 | Chugai Seiyaku Kabushiki Kaisha | FGFR3 fusion gene and drug that targets it |
| US9266892B2 (en) | 2012-12-19 | 2016-02-23 | Incyte Holdings Corporation | Fused pyrazoles as FGFR inhibitors |
| AR094812A1 (en) | 2013-02-20 | 2015-08-26 | Eisai R&D Man Co Ltd | DERIVED FROM MONOCYCLIC PYRIDINE AS AN FGFR INHIBITOR |
| SG10201708520YA (en) | 2013-04-19 | 2017-12-28 | Incyte Corp | Bicyclic heterocycles as fgfr inhibitors |
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| AU2014297298B2 (en) * | 2013-07-31 | 2019-10-17 | Chugai Seiyaku Kabushiki Kaisha | Pharmaceutical preparation comprising aminopyrazole derivative |
| CN110028491B (en) | 2013-10-25 | 2022-02-11 | 缆图药品公司 | Fibroblast growth factor receptor inhibitors |
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| US11104668B2 (en) * | 2013-12-13 | 2021-08-31 | Hoffmann-La Roche Inc. | Inhibitors of bruton's tyrosine kinase |
| DK3087986T3 (en) * | 2013-12-27 | 2019-12-02 | Chugai Pharmaceutical Co Ltd | MUTANT FGFR GATEKEEPERGEN AND ACTIVE SUBSTANCE AIMED AT THE SAME |
| WO2015108992A1 (en) | 2014-01-15 | 2015-07-23 | Blueprint Medicines Corporation | Heterobicyclic compounds and their use as fgfr4 receptor inhibitors |
| RU2016137179A (en) | 2014-03-31 | 2018-05-07 | Дебиофарм Интернэшнл Са | FGFR HYBRID PROTEINS |
| US9974785B2 (en) | 2014-07-08 | 2018-05-22 | Sunshine Lake Pharma Co., Ltd. | Aromatic heterocyclic derivatives and pharmaceutical applications thereof |
| KR102344105B1 (en) | 2014-08-18 | 2021-12-29 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | Salt of monocyclic pyridine derivative and crystal thereof |
| US10851105B2 (en) | 2014-10-22 | 2020-12-01 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
| MX2017010673A (en) | 2015-02-20 | 2018-03-21 | Incyte Corp | Bicyclic heterocycles as fgfr inhibitors. |
| WO2016134294A1 (en) | 2015-02-20 | 2016-08-25 | Incyte Corporation | Bicyclic heterocycles as fgfr4 inhibitors |
| MA41551A (en) | 2015-02-20 | 2017-12-26 | Incyte Corp | BICYCLIC HETEROCYCLES USED AS FGFR4 INHIBITORS |
| US10479780B2 (en) | 2015-06-17 | 2019-11-19 | Chugai Seiyaku Kabushiki Kaisha | Aminopyrazole derivatives |
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